Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) refers to a strategy involving the use of antiretroviral (ARV) drugs to decrease the risk of HIV infection in uninfected individuals whose behavior would combine with local HIV prevalence to place them at high risk of infection. In 2012, the use of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) in combination was approved by the US Food and Drug Administration for use as PrEP, based on the results of the iPrEx 1-3 study and Partners PrEP, 4 with the former showing a 44% reduction in the incidence of HIV transmission in men who have sex with men as compared with placebo treatment, when combined with a comprehensive package of prevention. Partners PrEP showed a 67-75% relative reduction in the incidence of HIV infection using TDF/FTC among heterosexual couples in sexual partnerships containing one seronegative partner.Although there is conceptual proof of PrEP in these specific contexts, recent negative results of two studies in women, FEMPrEP 5 and VOICE, 6 showed no evidence of benefit of daily oral TDF/FTC. These negative outcomes were later ascribed to suboptimal adherence to the dosing regimen, thus indicating the need for high motivation in order to attain prevention success. Therefore, durable adherence is critical for a successful long-term prevention strategy. 2,4,6 In addition, the potential for side effects and toxicities associated with the use of TDF/ FTC 2,7 remains a concern due to its widespread administration as HIV PrEP.An optimal PrEP therapy should be safe to administer and be readily distributed to the relevant target tissues in concentrations that are sufficient to provide protection against HIV infection. Ideally, PrEP agents should be characterized by convenient dosing and by routes of administration that do not depend on the recipient maintaining daily adherence to dosing.The nonnucleoside reverse-transcriptase inhibitor RPV is a diarylpyrimidine derivative that was approved by the Food and Drug Administration in 2011 for oral administration for the treatment of HIV infection in combination with other ARV drugs. 1,3 A parenteral formulation of rilpivirine (RPV-LA) with prolonged pharmacokinetic (PK) exposure is being developed, enabling improved adherence to ARV treatment over prolonged periods and having potential as an agent for HIV PrEP. 2,8,9 The potential advantages of a long-acting formulation include infrequent parenteral administration and a low potential for gastrointestinal side effects associated with lifelong oral ARV intake. Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervi...

Aims-To compare the serum concentrations of itraconazole and hydroxyitraconazole after treatment with itraconazole cyclodextrin solution and itraconazole capsules in human immunodeficiency virus (HIV) positive patients with oral candidosis. Methods-The pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole were assessed on days 1 and 7 of therapy in aquired immunodeficiency syndrome (AIDS) patients with oral candidosis taking either itraconazole solution or capsules and the serum concentrations (measured by high performance liquid chromatography) correlated with the clinical response to therapy. In addition, the in vitro susceptibility of Candida spp isolates taken from patients at the start of the therapy was assessed. Results-Nine of 16 patients treated with itraconazole capsules and eight of 15 treated with the solution responded to treatment. Three of the non-responders in each treatment group were infected with isolates resistant to itraconazole in vitro. Although with both preparations there was considerable inter-patient variability in the maximum recorded serum concentrations of itraconazole, they were significantly lower on day 1 and day 7 in those receiving capsules compared with those taking the solution. Patients unresponsive to therapy, but infected with susceptible isolates, had significantly lower concentrations of itraconazole and hydroxyitraconazole levels on days 1 and 7 than patients responding to treatment. However, patients infected with itraconazole resistant isolates (tested in vitro) failed to respond to treatment despite achieving similar serum concentrations of itraconazole and hydroxy-itraconazole to the responsive patients. For patients with in vitro susceptible isolates a serum itraconazole concentration of < 1000 nglml on day 7 was predictive of therapeutic failure (specificity 71%, sensitivity 100%). Conclusions-Itraconazole cyclodextrin solution achieves higher serum itraconazole and hydroxy-itraconazole concentrations than the capsule formulation in AIDS patients, and this is associated with improved efficacy.

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A case control study of AIDS related sclerosing cholangitis indicates that it has no overall influence on prognosis, but is responsible for a striking reversal of the usual inverse correlation of age and survival in HIV infection. Pain, the principal symptom, was controlled in surviving patients with analgesics alone. Twenty consecutive patients with AIDS related sclerosing cholangitis, defined from at least two characteristic lesions at endoscopic retrograde cholangiopancreatography, were followed for a minimum of 10 months or until death. Median age was 33-5 years (range 27-50). All had abdominal pain; 11 had diarrhoea. Alkaline phosphatase was >2X normal in 13, but the bilirubin was raised in only three. The median CD4 was 0*024X109/l (0.005-0.341). Thirteen had cryptosporidiosis, six had active cytomegalovirus, five had no gastrointestinal pathogen. Three patients are alive without AIDS related sclerosing cholangitis symptoms at 10, 11, and 21 months. Seventeen have died at median 7 (1-23) months. Cytomegalovirus therapy had no apparent influence. The initial CD4 was <0.11 in all those dying within six months, but correlation of CD4 with prognosis was otherwise poor. Controls, matched for age, CD4, and opportunistic infections had virtually identical overall outcome (median survival 7-5 months) and the expected worse prognosis with increasing age. Increasing age, however, appeared protective in AIDS related sclerosing cholangitis (r=+0.6; p<005): this is not explained by disproportionate degrees of immunosuppression, nor by opportunistic infections.

SUMMARY Early changes in coagulation were found in patients following a paracetamol overdose. Low levels of clotting factors II, V and VII were present within 24 hours of the overdose. As the levels of factor II correlated with plasma fibrinogen values at this time, it is possible that they were consumed in the process of intravascular coagulation, although this was not supported by the presence of raised titres of fibrin degradation products. The prothrombin time ratio was greater than 2-2 within 30 hours of ingestion of the overdose in all patients who eventually died, whereas it was less than this in those developing only moderate liver damage. The administration of fresh frozen plasma to patients did appear to reduce the maximum abnormality of the prothrombin time ratio, which was significantly less three days after the overdose in the group receiving fresh frozen plasma. However, the coagulation disturbance was of short duration, and the prothrombin time ratio had also returned to normal within one week of the overdose in the control patients, and the administration of fresh frozen plasma did not appear to reduce the morbidity or mortality in the treated patients.Paracetamol is frequently taken as an overdose in suicidal attempts, and hepatic damage of all grades of severity, from minor to fulminant hepatic failure, may result (Prescott, Wright, Roscoe, and Brown, 1971). In the latter group bleeding is often a major problem and is not infrequently the direct cause of death. It is thought to be due in part to low levels of clotting factors resulting both from impaired hepatic synthesis and increased consumption from intravascular coagulation (Rake, Flute, Shilkin, Lewis, Winch, and Williams, 1971). To replace this synthetic deficiency we have advocated the regular use offresh frozen plasma (FFP), although controlled evidence of its value was lacking.In this paper we describe detailed studies, including individual clotting factor assays, in 66 patients seen shortly after a paracetamol overdose, together with the results of a controlled trial of FFP in those patients in whom a severe coagulation disturbance subsequently developed.