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Objectives: To describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum., Patients and Methods: This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929., Results: Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported., Conclusions: Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir., Methods: This was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional., Results: 31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected., Conclusions: Despite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effective concentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis.
 ClinicalTrials.gov number NCT00825929.

Implementing clinical audit in a resource poor setting is often beset by practical issues. Out-sourcing the burden of data analysis may go a long way to facilitating regular audit in a resource poor setting. We investigated the feasibility of using an inexpensive 12-megapixel point-and-shoot digital camera to collect data from clinical notes in a format capable of being sent via secure electronic file transfer for remote analysis. We then performed a pilot audit on this data as a proof of principle.

Objective: To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum., Design: A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe., Methods: HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4-6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0., Results: Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71-0.83) for TDF area under the curve (AUC0-24 h); 0.81 (0.68-0.96) for TDF Cmax and 0.79 (0.70-0.90) for TDF C24 h and 0.75 (0.68-0.82) for FTC AUC0-24 h; and 0.87 (0.77-0.99) for FTC Cmax and 0.77 (0.52-1.12) for FTC C24 h. The viral load close to delivery was less than 200  copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported., Conclusion: Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.

Objectives: To determine differences in CYP2B6 loss of function (LoF) single nucleotide polymorphisms (SNPs) and haplotypes between Zimbabweans and Ugandans, and within Ugandan populations (Bantu and Nilotic)., Methods: Genetic epidemiological study enrolling adult black African Ugandan and Zimbabwean patients attending a UK HIV-1 clinic, irrespective of antiretroviral therapy status. Genomic DNA was extracted from whole blood and the presence of CYP2B6 alleles was determined by direct sequencing of all nine exons of the CYP2B6 gene. Blood was also collected, where appropriate, for determination of efavirenz concentrations. Frequency of SNPs in all patients and LoF haplotype frequencies were calculated. The relationship between the number of LoF haplotype alleles possessed and efavirenz trough concentration (ETC) was determined., Results: Thirty-six Zimbabweans and 74 Ugandans (58 Bantu and 16 Nilotic) were recruited. The definite haplotypes determined were *6, *18, *20 and *27 as LoF and *4 as gain of function. Among those with definite genotypes, the frequency of LoF alleles was 65% [95% confidence interval (95% CI): 51-80] of Zimbabweans versus 22% (95% CI: 12-31) of Ugandan Bantus (P = 10(-6)) and versus 39% (95% CI: 14-64) of Ugandan Nilotics (P = 0.09). Among the 19 patients with definite genotype and with available ETCs, log ETCs were associated with a greater number of LoF haplotype alleles [848 ng/mL (n = 12), 1069 ng/mL (n = 4) and 1813 ng/mL (n = 3) for 0, 1 or 2 LoF haplotypes, respectively (P = 0.016)]., Conclusions: Among Zimbabweans, LoF haplotypes constitute the majority of CYP2B6 alleles and are significantly higher in prevalence compared with Ugandans. Frequencies of LoF haplotypes and SNPs in Ugandan Nilotics appear to lie between those of Zimbabweans and Ugandan Bantus. These findings may have relevance to pharmacokinetics and dosing of efavirenz in African populations.

Background: To determine patient and treatment characteristics associated with vitamin D deficiency (VDD) in an UK inner city HIV-1-positive adult cohort., Methods: Two hundred twenty-seven HIV-positive patients attending prospectively for routine blood tests in winter had serum 25-hydroxyvitamin D and parathyroid hormone (PTH) concentrations and other routine chemistry measured. Those with and without VDD were defined as having serum 25-hydroxyvitamin D concentrations <50 nmol/L and >75 nmol/L, respectively. Characteristics were compared between patients with and without VDD. The effects of VDD, tenofovir use, and their interaction on chemical measures were investigated., Results: VDD was found in 57% (131 of 227) of patients. Independent associations included nonwhite ethnicity [adjusted odds ratio (95% confidence interval): 7.40 (2.52 to 21.7)], higher random blood glucose [2.38 (1.24 to 4.57) per mmol/L], higher estimated glomerular filtration rate [eGFR: 1.04 (1.01 to 1.06)], and higher PTH [1.19 (1.00 to 1.42)]. PTH was higher in those receiving tenofovir (median 7.2 pmol/L) than other patients (4.3; P < 0.001) overall, but high PTH with tenofovir occurred only in the context of VDD. Tenofovir use was not associated with serum creatinine or eGFR overall but interacted with vitamin D status (P = 0.05 and P = 0.08, respectively), being linked to somewhat higher creatinine and lower eGFR among patients without VDD but higher eGFR in VDD patients., Conclusions: 25(OH) VDD is associated with tenofovir-linked hyperparathyroidism and also with higher eGFR.

Objectives: Human leukocyte antigen (HLA)-B(*)5701 is strongly associated with developing a hypersensitivity reaction to abacavir (ABC) in White and Hispanic subjects. Across the UK, limited data exist on HLA-B(*)5701 prevalence in HIV-1-infected subjects. We determined HLA-B(*)5701 prevalence in the general HIV-1-infected population and in specific ethnic groups, particularly Black Africans who, in general, exhibit greater genetic diversity. We also compared HLA-B(*)5701 results obtained from local laboratories with those from a central provider., Design and Methods: Multi-centre, observational study. All HIV-1-infected adult individuals receiving care at participating centres were eligible, irrespective of treatment status or prior exposure to ABC. Subjects provided samples for HLA-B(*)5701 assessment by both local (blood) and central laboratories (buccal swabs). HLA-B(*)5701 prevalence was adjusted to represent the ethnic group composition of the general UK population, and by main ethnic group. RESULTS; From eight UK centres, 1494 subjects [618 (41%) White, 770 (52%) Black] were recruited. Eighty-nine per cent of Black subjects reported an immediate country of origin in Africa. Overall adjusted HLA-B(*)5701 prevalence was 4.55% [95% confidence interval (CI) 3.49% to 5.60%]. Among White subjects, prevalence was 7.93% (CI 5.80% to 10.06%). Among Black subjects, only two (both Ugandan) were HLA-B(*)5701 positive giving a rate of 0.26% (CI 0.07% to 0.94%)., Conclusions: HLA-B(*)5701 prevalence was similar to previously reported rates in White HIV-infected subjects but considerably lower than that reported in Black HIV-1-infected subjects, as a result of the large proportion of Black African subjects.

Objective: To identify opportunities for earlier HIV diagnosis within primary and secondary care settings in the UK in Africans with newly diagnosed HIV infection., Methods: A survey of newly diagnosed HIV-positive Africans attending 15 HIV treatment centres across London was conducted between April 2004 and February 2006. The survey consisted of a confidential self-completed questionnaire linked to clinician-completed clinical records., Results: A total of 263 questionnaires were completed, representing an uptake rate of 79.5% of patients approached and 49.8% (131/263) of participants presented with advanced HIV disease (CD4 cell count < 200 cells/mul at diagnosis). In the year prior to HIV diagnosis 76.4% (181/237) had seen their GP, 38.3% (98/256) had attended outpatient services, and 15.2% (39/257) inpatient services, representing missed opportunities for earlier HIV diagnosis. Of those attending GP services the issue of HIV and/or HIV testing was raised for 17.6% (31/176) and 37.1% (78/210) had a previous negative HIV test, 32.5% of these within the UK. Medical attention was sought for wide ranging reasons, often not obviously connected to underlying HIV status. Despite the population predominantly coming from countries of high HIV prevalence personal appreciation of risk was comparatively low and knowledge of benefits of testing lacking., Conclusion: Africans are accessing health services but clinicians are failing to use these opportunities effectively for preventive and diagnostic purposes with regards to HIV infection. Comparatively low appreciation of personal risk and lack of perceived ill health within this community means clinicians need to be more proactive in addressing HIV.

Objective: To examine the effect of early syphilis on blood and semen plasma HIV-1 viral loads and CD4 counts., Methods: In a retrospective case-control study, blood plasma HIV-1 viral loads and CD4 counts in cases during early syphilis (n = 63, 27 receiving antiretroviral therapy) were compared to those before and after syphilis and with controls with non-systemic acute sexually transmitted infections (STI) (n = 104, 39 receiving antiretroviral therapy). In a prospective substudy in those not receiving antiretroviral therapy, semen plasma viral loads during early syphilis (n = 13) were compared with those 1 month, 3 months, and 6 months after treatment for syphilis and with controls with no STIs (n = 20)., Results: Retrospective study: CD4 counts were similar in cases (median 410, n = 139 counts) during early syphilis compared to before (485, n = 80) and after (475, n = 88). In a secondary analysis, a drop in CD4 count (21%) among those with early latent syphilis was observed compared with controls. Blood plasma viral loads did not change significantly overall or in those with primary, secondary, or early latent syphilis. Effects were similar on or off antiretroviral therapy. Prospective study: blood and semen viral loads were slightly higher in cases compared with controls but treatment of early syphilis did not reduce either., Conclusions: We detected no association between early syphilis and changes in blood or semen viral load or CD4 count. Increased HIV-1 infectivity associated with early syphilis is unlikely to be associated with increased levels of HIV-1 RNA in blood or semen.

Sexually transmitted infections may enhance the sexual transmission of HIV-1. It is possible that loss of virological control in patients with such infections receiving antiretroviral therapy (ART) may even facilitate the transmission of drug-resistant HIV. We have recently demonstrated that in those on maximally suppressive ART this effect is reduced. We have examined the virus obtained from the blood plasma and seminal plasma of six HIV-1-infected men receiving poorly suppressive ART with acute urethritis for the presence of drug resistance-associated mutations. In four men with gonorrhoea the blood and seminal plasma HIV-1 had mutations conferring reduced susceptibility to one or more available drugs. In one of these men the viral load of drug-resistant virus in seminal plasma was 20-fold higher during gonorrhoea than following antibiotic treatment, with no change in blood plasma viral load. We conclude that in the presence of suboptimal ART, sexually transmitted infections may enhance the spread of drug-resistant HIV-1.

Two HIV infected patients presented with peripheral neuropathy, in one patient this was originally ascribed to HIV associated mononeuritis multiplex and in the other to stavudine. Investigations confirmed these diagnoses and in both cases genetic analysis identified a second hereditary aetiology: in the first patient hereditary neuropathy with liability to pressure palsies and in the second hereditary motor and sensory neuropathy.

Background: High seminal plasma HIV-1 RNA loads (SVL) have been reported during gonococcal, non-gonococcal and chlamydial urethritis in patients not taking antiretroviral therapy., Objective: To examine if urethritis leads to increased SVL in HIV-positive patients taking antiretroviral therapy., Methods: Men who had been taking therapy for at least 3 months were recruited: 24 had urethitis (PWU) and 16 were without urethritis (controls). At three visits, 1 week apart, blood plasma viral load (BVL) and SVL were assayed by quantitative polymerase chain reaction or the NASBA assay., Results: Most subjects had undetectable SVL (18 PWU, 13 controls). Among those with undetectable BVL prior to first study visit, virus was undetectable in semen in 5/5 episodes of chlamydial urethritis, 6/7 episodes of non-gonococcal urethritis and 4/5 cases of gonococcal urethritis. Two PWU with undetectable BVL just prior to the first study visit had low to moderate SVL, which became undetectable by visit 2 following treatment. Of nine subjects with detectable SVL, eight had detectable BVL (3/3 controls and 5/6 PWU). Of these, 1/3 controls and 4/5 PWU (all with gonococcal urethritis) had poorly controlled BVL just prior to the first study visit. These four PWU had high SVL and one had higher levels in semen than in blood. This patient's SVL was reduced more than 20-fold following treatment for gonococcal urethritis., Conclusions: Effective antiretroviral therapy appeared to limit the effect of urethritis on SVL. When BVL was poorly controlled by antiretroviral therapy, high SVL occurred during gonococcal urethritis, increasing the potential risk of transmitting both wild type and drug resistant strains of HIV-1.