V3-Loop genotypes do not predict maraviroc susceptibility of CCR5-tropic virus or clinical response through week 48 in HIV-1-infected, treatment-experienced persons receiving optimized background regimens.

Viruses from 15 of 35 maraviroc-treated participants with virologic failure and CCR5-tropic (R5) virus in the MOTIVATE studies at Week 24 had reduced maraviroc susceptibility. On-treatment amino acid changes were observed in the viral envelope glycoprotein 120 third variable (V3)-loop stems and tips and differed between viruses. No amino acid change reliably predicted reduced susceptibility, indicating that resistance was genetic context-dependent. Through Week 24, poor adherence was associated with maraviroc-susceptible virologic failure, whereas reduced maraviroc susceptibility was associated with suboptimal background regimen activity, highlighting the importance of overall regimen activity and good adherence. Predictive values of pretreatment V3-loop sequences containing these Week 24 mutations or other variants present at >3% in pretreatment viruses of participants with virologic failure at Week 48 were retrospectively assessed. Week 48 clinical outcomes were evaluated for correlates with pretreatment V3-loop CCR5-tropic sequences from 704 participants (366 responders; 338 virologic failures [83 with R5 virus with maraviroc susceptibility assessment]). Seventy-five amino acid variants with >3% prevalence were identified among 23 V3-loop residues. Previously identified variants associated with resistance in individual isolates were represented, but none were associated reliably with virologic failure alone or in combination. Univariate analysis showed virologic-failure associations with variants 4L, 11R, and 19S (P < 0.05). However, 11R is a marker for CXCR4 tropism, whereas neither 4L nor 19S was reliably associated with reduced maraviroc susceptibility in R5 failure. These findings from a large study of V3-loop sequences confirm lack of correlation between V3-loop genotype and clinical outcome in participants treated with maraviroc.Clinical trial registration numbers (ClinicalTrials.gov): NCT00098306 and NCT00098722.

Assessment of Maraviroc Exposure-Response Relationship at 48 Weeks in Treatment-Experienced HIV-1-Infected Patients in the MOTIVATE Studies.

Efficacy exposure-response relationships of the CCR5 antagonist maraviroc were evaluated across two phase III clinical trials. This post-hoc analysis used 48-week efficacy data from 841 treatment-experienced patients infected with CCR5-tropic human immunodeficiency virus type 1 (HIV-1), identified by the enhanced sensitivity Trofile assay. Probability of treatment success (viral RNA <50 copies/ml) was modeled using generalized additive logistic regression, testing exposure, clinical, and virologic variables. Prognostic factors for treatment success (in decreasing order of Akaike information criterion (AIC) change) were: maraviroc treatment, high-weighted overall susceptibility to background treatment, absence of an undetectable maraviroc concentration, high baseline CD4 count (BCD4), low viral load (VL), race (other than black), absence of non-R5 baseline tropism (BTRP), and absence of fosamprenavir (FPV). No concentration-response relationship was found with treatment (maraviroc vs. placebo) and presence/absence of undetectable maraviroc concentration (adherence marker) in the model. The maraviroc doses studied (300 or 150 mg with potent CYP3A4 inhibitors once (q.d.)/twice daily (b.i.d.)) deliver concentrations near the top of the concentration-response curve.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e64; doi:10.1038/psp.2013.42; published online 14 August 2013.

Counting the costs: comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa.

BACKGROUND: In South Africa, where health care resources are limited, it is important to ensure that drugs provision and use is rational. The Essential Drug List includes depot medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN) as injectable progestagen-only contraceptives (IPCs), and both products are extensively used. OBJECTIVES AND METHODS: Utilisation patterns of the injectable contraceptive products DMPA and NET-EN are compared in the context of current knowledge of the safety and efficacy of these agents. Utilisation patterns were analysed by means of a Pareto (ABC) analysis of IPCs issued from 4 South African provincial pharmaceutical depots over 3 financial years. A case study from rural KwaZulu-Natal, South Africa, is used to examine utilisation patterns and self-reported side effects experienced by 187 women using IPCs. RESULTS: IPCs accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from 2 depots increased over the 3-year period. Since DMPA was cheaper, if all NET-EN clients in the 1999/2000 financial year (annualised) had used DMPA, the 4 depots could have saved 4.95 million South African Rands on product acquisition costs alone. The KZN case study showed slightly more NET-EN (54%) than DMPA (46%) use; no significant differences in self-reported side effects; and that younger women were more likely to use NET-EN than DMPA (p = 0.0001). CONCLUSIONS: Providing IPCs on the basis of age is not appropriate or cost effective. Rational use of these products should include consideration of the cost of prescribing one over another.

Emergency contraception in South Africa: knowledge, attitudes, and use among public sector primary healthcare clients.

To determine knowledge of, attitudes toward, and use of emergency contraception (EC), interviews were held with 1068 clients of 89 public sector primary healthcare facilities in two urban and two rural areas of South Africa. Only 22.8% of the clients had heard of EC. Awareness was significantly lower in the most rural area and among older, less educated women. Knowledge of EC was superficial, with 47.1% unsure of the appropriate interval between unprotected intercourse and starting EC and 56.6% not knowing whether it was available at the clinic. Few (9.1%) of those who knew of EC had used it. After explaining EC, attitudes toward its use were found to be positive, with 90.3% indicating that they would use it if needed. Awareness was lower than in developed countries, but higher than in other developing countries. Findings indicate that if women know of EC, where to get it, and how soon to take it, they would use it if needed.

Intravenous and intramuscular magnesium sulphate regimens in severe pre-eclampsia.

Patients with severe pre-eclampsia were randomised to receive magnesium sulphate according to an intramuscular (IM) (N = 9) or an intravenous (i.v.) (N = 8) regimen. The IM regimen consisted of a loading dose of 14 g (4 g i.v. and 10 g IM) followed by 5 g 4-hourly. Patients given the IV regimen received a 6 g i.v. loading dose followed by a maintenance infusion of 2 g/h. Clinical outcome, laboratory parameters and serum magnesium levels were recorded for both groups. There were no significant differences between groups with regard to clinical outcome of either mother or child. Similar average serum magnesium concentrations were produced by the regimens the only significant difference was that fluctuations in magnesium levels were greater with the IM than the i.v. regimen. None of the patients had seizures despite levels mostly below 2 mmol/l.

Earlier discharge with community-based intervention for low birth weight infants: a randomized trial.

BACKGROUND: Prolonged hospitalization of low birth weight infants increases the risk of medical and psychosocial complications. The feasibility of earlier discharge with community-based follow-up of infants of < or = 2000 g birth weight, without the use of home apnea monitors, was investigated. METHODS: One hundred infants of < or = 2000 g birth weight were randomized to either an intervention or control group. Intervention infants were discharged when readiness criteria were met. Based on assessed need, intervention group families received public health nursing and homemaker services for up to 8 weeks. Control infants were discharged to their homes at the discretion of the attending physician. All infants were assessed blindly at age 1 year with the Bayley and Home Observation for Measurement of the Environment (HOME) scales. RESULTS: There were no group differences in baseline infants' characteristics or in neonatal complications. Infants in the intervention group were discharged from the hospital at an earlier postconceptional age (mean +/- SD 36.6 +/- 1.5 weeks vs 37.3 +/- 1.6 weeks; P < .04). Median length of hospital stay (23 days vs 31.5 days) and mean weight at the time of discharge (2200 +/- 288 g vs 2275 +/- 301 g) were lower, but not significantly, for infants in the intervention group. A secondary analysis by birth weight strata (< or = 1500 g and 1501 through 2000 g) revealed that the most significant reductions in hospital stay and weight at discharge were realized in infants of 1501 through 2000 g birth weight. The persistence of apneic episodes and need for electronic monitoring prevented earlier discharge of infants of < or = 1500 g birth weight. Postdischarge services to the intervention group included 185 public health nurse home visits (3.8 +/- 0.91), 410 phone contacts (8.4 +/- 5), and 2298 homemaker hours (46 +/- 78) of service. At 1 year, there were no deaths and no group differences in rehospitalization rates, use of ambulatory services, or Bayley scores. Intervention families had significantly higher 1-year HOME scores. Minimum cost of hospital care was $873 per day, while the total cost of community-based services averaged $626 per infant. CONCLUSIONS: A significant reduction in average length of hospital stay was achieved for infants of 1501 through 2000 g birth weight. Earlier discharge of infants weighing < or = 1500 g at birth was hampered by persistent apneic episodes and feeding difficulties. A community-based program designed to provide individualized support and education for families of low birth weight infants was cost-effective and had a positive influence on the home environment.

The efficacy of phenytoin in relation to serum levels in severe pre-eclampsia and eclampsia.

OBJECTIVES: To investigate the efficacy of phenytoin in relation to total and free serum levels in patients with severe pre-eclampsia and eclampsia. DESIGN: Prospective descriptive study. SETTING: Labour Ward, King Edward VIII Hospital, Durban, South Africa. Tertiary referral centre serving an underprivileged community. SUBJECTS: Eleven patients admitted with a hypertensive crisis. Four patients had eclampsia and 7 had impending eclampsia. MAIN OUTCOME MEASURES: Free and total phenytoin levels; efficacy of phenytoin as an anticonvulsant and side-effects of therapy. RESULTS: Although total phenytoin levels were within the therapeutic range, free phenytoin levels were abnormally high in all patients. Three patients (2 with eclampsia and 1 with imminent eclampsia) each had a seizure after phenytoin treatment had been initiated. CONCLUSION: Neither total nor free phenytoin levels were good predictors of seizure control. It is postulated that the poor performance of phenytoin as an anticonvulsant in severe eclampsia may relate to inadequate distribution of the drug to the brain as a result of cerebral oedema and poor cerebral perfusion rather than paradoxical seizure activity associated with high free phenytoin levels.