Jeannine F. J. B. Nellen

The AmRo study: pregnancy outcome in HIV-1-infected women under effective highly active antiretroviral therapy and a policy of vaginal delivery.

Objective  To explore pregnancy outcome in HIV‐1‐positive and HIV‐negative women, and mother‐to‐child transmission (MTCT) according to mode of delivery under effective highly active antiretroviral therapy (HAART).

Virologic and immunologic response to highly active antiretroviral therapy in indigenous and nonindigenous HIV-1-infected patients in The Netherlands

Objective:To compare the results of antiretroviral treatment (highly active antiretroviral therapy [HAART]) in indigenous Dutch (ID) and nonindigenous HIV-1–infected patients in Amsterdam, the Netherlands. We focused on the largest groups of nonindigenous people visiting our outpatient clinic: patients from other industrialized countries (western), from Surinam/Netherlands Antilles (SNA), and from sub-Saharan Africa (SSA). Design:Retrospective cohort analysis of 692 therapy-naive HIV-1–positive individuals who visited our outpatient clinic for the first time between July 1, 1996 and December 31, 2001. Methods:We compared the groups at the time of their first visit to our clinic; at the start of HAART; and according to the virological, immunologic, and clinical treatment response during the 96 weeks after the start of HAART. Results:Of the patients starting antiretroviral therapy, 362 were ID, 84 were western, 72 were from SNA, and 110 were from SSA. SNA and SSA patients had a lower CD4 cell count at first visit (ID = 330 cells/mm3, western = 330 cells/mm3, SNA = 250 cells/mm3, and SSA = 170 cells/mm3; P = 0.0002). Treatment in SNA and SSA patients was also started at a lower CD4 cell count, but the plasma HIV-1 RNA level was comparable. After the start of HAART, a similar rise in CD4 cell count was seen in the 4 groups (P = 0.33), but the baseline difference in CD4 cell count remained present during the follow-up period of 96 weeks. After adjusting for variables potentially influencing treatment outcome, the proportion of patients not reaching a plasma HIV-1 RNA level <400 copies/mL was not different for the 4 groups in contrast to the percentage not reaching a plasma HIV-1 RNA level <50 copies/mL (at 48 weeks: ID = 4.8%, western = 27.5%, SNA = 23.1%, and SSA = 24.2%; P = 0.017 over the 96-week time period). After the start of HAART, nonindigenous patients also more often had progression to Centers for Disease Control and Prevention (CDC) stage C or died (P = 0.006). Conclusions:In nonindigenous patients, treatment with HAART was equally successful in terms of the increase in CD4 cell count but was substantially less effective in achieving a plasma HIV-1 RNA level below 50 copies/mL. Further investigations should explore differences in adherence and pharmacokinetics in these patient groups.

Nelfinavir Plasma Concentrations Are Low during Pregnancy

Plasma nelfinavir concentration ratios (CRs) were calculated for all pregnant (n=27) and nonpregnant (n=48) human immunodeficiency virus type 1-infected women receiving the drug who visited our outpatient clinic. In pregnant women, mean and median nelfinavir CRs were significantly lower (P=.02 and P=.04, respectively), and 51% of the CRs were below the clinically relevant threshold of 0.90, compared with 35% of the CRs in nonpregnant women. After we adjusted for confounders, we found that the mean nelfinavir CR was 34% lower in pregnant women (P=.02). With targeted interventions, subsequent CRs in pregnant women showed a significant increase (median increase, 0.31; P=.01).

HIV status disclosure among HIV-positive African and Afro-Caribbean people in the Netherlands

Abstract HIV status disclosure is often characterized as a dilemma. On the one hand, disclosure can promote health, social support, and psychological well-being. On the other, disclosure can lead to stigmatization, rejection, and other negative social interactions. Previous research has shown that HIV status disclosure is a reasoned process whereby the costs and benefits to oneself and to others are weighed. As such, understanding disclosure requires understanding the reasons for and against disclosure employed by people living with HIV (PLWH). In this study, disclosure among a population disproportionately affected by HIV in the Netherlands, namely African and Afro-Caribbean diaspora, was investigated. Reasons for nondisclosure were fear of stigmatization, previous negative experiences with disclosure, having observed the stigmatization of other PLWH, shame, the desire to protect others – particularly ones children and family – from stigmatization by association and/or worrying, and the belief that ones HIV status is a private matter. Participants reported disclosing because they were in a close and supportive relationship, disclosure led to emotional release, disclosure could lead to emotional or financial support, they felt a perceived duty to inform, and they had a desire to educate others about sexual risk-taking. The findings suggest that stigma plays an important role in disclosure decisions among these populations. They further point to a need for HIV-related stigma reduction interventions in African and Afro-Caribbean communities and culturally sensitive counseling for PLWH whereby caregivers do not automatically assume that disclosure is best but rather provide a safe environment in which the costs and benefits of disclosure can be weighed and strategies for disclosure can be developed, if perceived as beneficial by PLWH.

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

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 Effect on Treatment Adherence of Administering Drugs as Fixed-Dose Combinations versus as Separate Pills: Systematic Review and Meta-Analysis

Administering drugs as fixed-dose combinations (FDCs) versus the same active drugs administered as separate pills is assumed to enhance treatment adherence. We synthesized evidence from randomized controlled trials (RCTs) about the effect of FDCs versus separate pills on adherence. We searched PubMed for RCTs comparing a FDC with the same active drugs administered as separate pills, including a quantitative estimate of treatment adherence, without restriction to medical condition. The odds ratio (OR) of optimal adherence with FDCs versus separate pills was used as common effect size and aggregated into a pooled effect estimate using a random effect model with inverse variance weights. Out of 1258 articles screened, only six studies fulfilled inclusion criteria. Across medical conditions, administering drugs as FDC significantly increased the likelihood of optimal adherence (OR 1.33 (95% CI, 1.03–1.71)). Within subgroups of specific medical conditions, the favourable effect of FDCs on adherence was of borderline statistical significance for HIV infection only (OR 1.46 (95% CI, 1.00–2.13)). We observed a remarkable paucity of RCTs comparing the effect on adherence of administering drugs as FDC versus as separate pills. Administering drugs as FDC improved medication adherence. However, this conclusion is based on a limited number of RCTs only.

Which method of adherence measurement is most suitable for daily use to predict virological failure among immigrant and non-immigrant HIV-1 infected patients?

Abstract In industrialized countries, virological failure occurs more often among HIV-infected immigrant patients. Non-adherence is the most credible explanation. We compared adherence of immigrant patients with that of non-immigrant patients in the Netherlands, and investigated which method of adherence measurement is most suitable for daily use to predict virological treatment failure: testing knowledge of the current regimen, a quantitative adherence interview, pharmacy prescription refill ratio (dispensed medication divided by prescribed medication, DM/PM), and plasma drug levels. Included were 61 immigrants and 81 non-immigrants. Virological failure did occur more often in immigrants than in non-immigrants (19.7% (12/61) versus 8.6% (7/81), p=0.056), especially among previously naïve patients (19.6% (11/56) versus 0% (0/54), p<0.01). There were no differences between both groups on any of the four adherence measures. Virological failure was associated with reporting stopping medication when not feeling well (OR=12, 95%CI=1.9–77.7, p=0.02), and, among naive patients, also with a DM/PM < 0.85 (Odds Ratio=5.1, 95%Confidence Interval=1.2–22.3, p=0.03). Although our study confirmed a much higher virological failure rate among immigrants, we were unable to identify clear differences in adherence between immigrants and non-immigrant patient, although virological failure was associated with stopping medication when not feeling well and a low DM/PM. Unstructured treatment interruptions are a likely explanation of the findings. Interventions should be aimed at preventing patients to stop medication. A DM/PM below 0.85 can be indicative for patients who did stop medication and are at risk for virological failure.

Race is not associated with nevirapine pharmacokinetics.

The effect of race on the pharmacokinetics of nevirapine was investigated in a nonselected population. Included patients were ambulatory HIV-1-infected patients from the outpatient clinics of the Academic Medical Center and the Slotervaart Hospital, Amsterdam, The Netherlands. All patients were using nevirapine as part of their antiretroviral regimen and had at least one plasma concentration available for analysis. From the included patients, gender, age, race, hepatitis C status, baseline ASAT value, and body weight were obtained. The nonlinear mixed-effect modeling program (NONMEM) version V 1.1 was used for all analyses. Population pharmacokinetic parameters [clearance (CL/F), volume of distribution (V/F), absorption rate constant (ka)] and interindividual (IIV) and interoccasion variability (IOV) were estimated. The influence of race on the CL/F of nevirapine was tested as Negroid race versus the other races, Asian race versus the other races, and the Negroid and the Asian races as separate variables versus the Caucasian race.A database of 1732 nevirapine plasma concentrations of 383 HIV-1-infected individuals collected during 1186 outpatient clinic visits was available for this analysis. The conclusion of this study is that race is not associated with the pharmacokinetics of nevirapine, and thus requires no dose adaptations.

Hcv coinfection, an important risk factor for hepatotoxicity in pregnant women starting antiretroviral therapy

OBJECTIVES This retrospective cohort study evaluated the risk of hepatotoxicity in HIV-1 positive pregnant and non-pregnant women starting combined ART. METHODS Data were used from the ATHENA observational cohort. The study population consisted of HIV-1 infected, therapy naïve, pregnant and non-pregnant women, followed between January 1997 and February 2008. Demographic, treatment and pregnancy related data were collected. Risk of hepatotoxicity was determined using univariate and multivariate logistic regression. Analyses were adjusted for age, region of origin, baseline HIV-RNA levels and CD4 cell counts, cART regimen and hepatitis B and C coinfection. ALT and AST values of more than 5 times ULN were considered as hepatotoxicity. RESULTS Four-hundred and twenty-five pregnant and 1121 non-pregnant women were included. Independent risk factors of hepatotoxicity in all women were the presence of detectable HCV RNA (OR 5.48, 95% CI 2.25-13.38, p<0.001) and NVP use (OR 2.63, 95% CI 1.54-4.55, p<0.001). Stratified for pregnancy, the adjusted risk of hepatotoxicity was significantly associated with HCV coinfection only during pregnancy (OR 23.53, 95% CI 4.69-118.01, p<0.001). NVP use is related to hepatotoxicity in pregnant (OR 5.26, 95% CI 1.61-16.67, p<0.005) as well as in non-pregnant women (OR 2.13, 95% CI 1.11-4.00, p=0.02). CONCLUSION HCV coinfection and NVP use are associated with a higher risk of cART induced hepatotoxicity in pregnant women.

Steady-state nevirapine plasma concentrations are influenced by pregnancy.

Optimal plasma concentrations of antiretroviral drugs are required during pregnancy to treat maternal HIV infection and prevent mother‐to‐child transmission. We investigated the effect of pregnancy on nevirapine (NVP) plasma concentrations.