David Hawkins

A controlled trial of zidovudine in primary human immunodeficiency virus infection.

BACKGROUNDnIt is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis.nnnMETHODSnTo assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months.nnnRESULTSnThe mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (+/- SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P = 0.009 by the log-rank test). After adjustment for the base-line CD4 cell count, the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, -1.4 to 19.1) during the first six months of the study, whereas those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 percent confidence interval, 5.2 to 18.7), for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P = 0.001).nnnCONCLUSIONSnAntiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women 2008.

u2003

Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission. British HIV Association

Aims of the guidelines These guidelines, drawn up by a multidisciplinary group of clinicians and lay workers active in the management of pregnant women infected with HIV, aim to give up‐to‐date information on interventions to reduce the risk of mother to child transmission of the virus. The evidence on the use of interventions to prevent mother to child transmission of HIV has been graded according to the strength of the data as per the definitions of the US Agency for Health Care Policy and Research [ 1 ]. Weighted evidence on the use of combination antiretroviral therapy (ART) for the treatment of HIV infection per se is presented in the BHIVA guidelines for adults [ 2,3 ]. The highest level evidence (i.e. randomised controlled trials (RCTs) or large, well conducted meta‐analyses) is only available for formula feeding, prelabour caesarean section and zidovudine monotherapy. The need to treat mothers for HIV infection has led to the widespread use of ART in pregnancy which in turn results in new questions such as how to deliver when the mother, on therapy, has no detectable plasma viraemia with the most sensitive assays. In addressing many common and/or difficult clinical scenarios in the absence of ‘best evidence’ the guidelines rely heavily on ‘expert opinion’.

When should HAART be initiated in pregnancy to achieve an undetectable HIV viral load by delivery

Background:HAART dramatically reduces mother-to-child transmission of HIV allowing vaginal delivery if the viral load is low. This study provides data for the optimum timing of short-term HAART in pregnancy. Methods:Retrospective multicentre cohort study of pregnant women commencing HAART in London and Brighton, UK. Demographics, gestation, drug class, CD4 cell count, and viral load results were collated. Survival curves for reaching a viral load less than 50u200acopies/ml were stratified by initial HIV viral load. Coxs proportional hazards regression model was adjusted for demographics and immunovirological parameters. Results:Viral load was less than 50u200acopies/ml in 292 of 378 pregnancies (77.2%) by delivery. Pretreatment viral load was associated with the time taken, and the proportion achieving a viral load less than 50u200acopies/ml at (Pu200a⩽u200a0.001). When baseline viral load was less than 10u200a000u200acopies/ml, gestational age at HAART initiation did not affect success up to 26.3 weeks gestation. When viral load was more than 10u200a000u200acopies/ml, deferring HAART past 20.4 weeks reduced the probability of reaching less than 50u200acopies/ml by delivery (Pu200a=u200a0.011). When baseline viral load was more than 100u200a000u200acopies/ml the likelihood of reaching a viral load of less than 50u200acopies/ml was low (37%: hazard ratio 0.31), and dependent on the length of time on HAART. The hazard ratio for a nonnucleoside reverse transcriptase inhibitor regimen achieving a viral load less than 50u200acopies/ml compared with a protease inhibitor was 0.7 (95% confidence interval 0.52–0.94). Conclusion:With a viral load more than 10u200a000u200acopies/ml and especially with a viral load more than 100u200a000u200acopies/ml, the probability of achieving either less than 50u200acopies/ml by the time of delivery is compromised by delaying initiation of short-term highly active antiretroviral therapy beyond 20.4 weeks gestation. Current UK and other guidelines for when to commence START may therefore limit the chance of vaginal delivery.

The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women

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 300u200amg; equivalent to 245u200amg tenofovir disoproxil) and/or emtricitabine (FTC 200u200amg) 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 (AUC0–24u200ah); 0.81 (0.68–0.96) for TDF Cmax and 0.79 (0.70–0.90) for TDF C24u200ah and 0.75 (0.68–0.82) for FTC AUC0–24u200ah; and 0.87 (0.77–0.99) for FTC Cmax and 0.77 (0.52–1.12) for FTC C24u200ah. The viral load close to delivery was less than 200u200acopies/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.

Survival following HIV infection of a cohort followed up from seroconversion in the UK.

Objectives: To estimate changes over calendar time in survival following HIV seroconversion in the era of HAART and to provide updated survival estimates. Methods: Using data from a UK cohort of persons with well estimated dates of HIV seroconversion, we analysed time from seroconversion to death from any cause using Cox models, adjusted for prognostic factors. Kaplan–Meier methods were then used to determine the expected survival in each calendar period. Results: 2275 seroconverters were included with 18 695 person-years of follow up. A total of 444 (20%) died. The relative risk of death, compared with pre-1996, decreased over time to 0.63 [95% confidence interval (CI), 0.48–0.81], 0.24 (0.17–0.34), 0.14 (0.10–0.21), 0.08 (0.05–0.13) and 0.03 (0.02–0.06) in 1996–1997, 1998–1999, 2000–2001, 2002–2003 and 2004–2006, respectively. An elevated risk of death was associated with older age at seroconversion [hazard ratio (HR), 1.49; 95% CI, 1.34–1.66 per 10-year increase] and HIV infection through injecting drug use (HR, 1.53; 95% CI, 1.17–2.00). In 2000–2006, the proportion of individuals expected to survive 5, 10 and 15 years following seroconversion was 99%, 94% and 89%, respectively. Conclusions: Survival following HIV seroconversion has continued to improve over calendar time in our cohort, even in the more recent years of HAART availability. HIV seroconverters, by definition identified early in their infection, are likely to have the greatest opportunity for intervention; if similar high survival expectations are to be seen in the wider HIV-infected population, early diagnosis is likely to be crucial.

Pregnant women with HIV infection can expect healthy survival: three-year follow-up.

Objectives:To document postpartum disease-free survival of HIV-infected women taking antiretroviral therapy (ART) during pregnancy. Methods:Laboratory and clinical data were collected on all HIV-infected pregnant women delivering from 1998 to 2002 and followed up until September 2004 at 6 hospitals in London. Mothers were grouped according to receipt of zidovudine monotherapy (ZDVm), highly active antiretroviral therapy (HAART) given during and continued after pregnancy (cHAART), and short-term HAART given during pregnancy and discontinued on delivery (START). Results:Eight-five women took ZDVm, 155 took cHAART, and 71 took START. The mean follow-up for all mothers was 33 months, with a total of 847 person-years. At the first antenatal clinic (ANC) visit, 72% of women were in Centers for Disease Control and Prevention (CDC) stage A, 85% were treatment naive, and the ZDVm group had a median HIV viral load (VL) 10-fold less than those mothers who started HAART during pregnancy. At last follow-up, 1 patient had died and 6 (1.9%) had progressed to CDC stage C; 62% of all women, including a quarter of the ZDVm group, were receiving HAART for their own health; and 83% of all mothers had a VL <50 HIV RNA copies/mL of plasma regardless of whether they were on treatment or not. Conclusions:The median-term postpartum prognosis of HIV-infected pregnant women with access to HAART is good. Exposure to short-course ZDVm or START during pregnancy did not jeopardize their response to subsequent therapy.

Acute Renal Failure and Nephrotic Syndrome after Angiocardiography with Meglumine Diatrizoate

RENAL complications of angiography are rare.1 2 3 4 5 In the following case oliguria was followed by the development of a nephrotic syndrome and subsequent recovery. Case Report L.L., a 49-year-old man, was admitted to the hospital with acute pulmonary edema on January 12, 1970. Aortic insufficiency was diagnosed, and he responded to treatment with digitalis and diuretics. The blood urea nitrogen (BUN) was 11 mg, and the serum creatinine 1 mg per 100 ml. Urinalysis gave normal results. On January 27, he underwent uneventful cardiac catheterization, receiving 157 ml of meglumine diatrizoate (Renografin 70) for angiocardiography. After the procedure he was anuric .xa0.xa0.

Randomised, Multicentre Phase III Study of Saquinavir plus Zidovudine plus Zalcitabine in Previously Untreated or Minimally Pretreated HIV-Infected Patients

AbstractBackground: PISCES (SV14604) was the largest study of antiretroviral therapy to assess clinical end-points. The study data provides a repository of important information, much of which remains relevant today. This paper reviews the results of the PISCES study, placing the findings in context with today’s treatment practices.n Objective: To determine the antiretroviral efficacy of saquinavir hard gelatin capsule (SQV; Invirase®) plus two nucleoside analogues [zidovudine (ZDV) and zalcitabine (ddC)] using clinical end-points.n Design: Prospective, randomised, double-blind international study.n Patients: HIV-1-infected individuals (CD4 50 to 350 cells/μl) who were anti-retroviral-naïve or minimally pretreated with zidovudine (ZDV; ≤16 weeks) were randomised.n Interventions: Patients received: (i) SQV + ZDV + ddC, (ii) SQV + ZDV, (iii) ZDV + ddC, or (iv) ZDV for ≥80 weeks or until the common closure date, at daily oral dosages of SQV 1800mg, ddC 2.25mg and ZDV 600mg. After 14 months, ZDV monotherapy patients were reallocated to receive additional SQV + ddC in a double-blinded manner.n Main Outcome Measure: Time to clinical end-point of first AIDS-defining event (ADE) or death.n Results: A total of 3591 patients were randomised, and 3485 received therapy. Median duration of study therapy was 58.4 to 63.3 weeks and mean duration of follow-up was 73.9 to 75.6 weeks. The time to first ADE or death was significantly reduced with triple therapy relative to ZDV + ddC (p = 0.0001, log rank test). The proportion of patients progressing to the primary clinical end-point was 8.0% for the triple therapy group compared with 15.1 % for ZDV + ddC. Initiating triple therapy reduced the risk of progression by 50% relative to ZDV + ddC [risk ratio 0.502; (95% CI 0.379-0.663) p = 0.0001). Patients with prior ZDV therapy for <8 weeks achieved the greatest clinical benefit. HIV-1 RNA was reduced more by triple therapy than by either dual therapy (p = 0.0001), and this reduction explained 64% of the treatment effect. In an exploratory analysis, the primary end-point was reached by 8.0% of patients receiving immediate triple therapy, compared with 17.8% receiving initial ZDV monotherapy followed by triple therapy (p = 0.0001).n Conclusions: This study was the first to show the benefit of triple therapy over dual therapy using clinical outcome measures; treatment with SQV + ZDV + ddC producing a statistically significant prolongation of time to first ADE or death in antiretroviral-naïve/minimally pretreated patients, compared with combined nucleoside analogues only. The study also confirms the outcome benefit (time to first ADE or death) of immediate triple therapy over delayed triple therapy and the prognostic value of monitoring HIV-1 RNA (but not CD4 count). The potential of patient/clinician perception of therapy to influence study outcome was also demonstrated.

Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women

OBJECTIVESnTo describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum.nnnPATIENTS AND METHODSnThis 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.nnnRESULTSnTwenty-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.nnnCONCLUSIONSnDarunavir 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.