Montserrat Lonca

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients.

Background: Current therapies for chronic hepatitis C virus (HCV) in HIV co-infected patients have a low success rate and are poorly tolerated. We have evaluated the efficacy and safety of interferon alfa-2b (IFN) + ribavirin (RBV) versus pegylated interferon alfa-2b (PEG-INF) + RBV. Methods: Randomized, single-centre, open-label clinical trial including patients with: detectable HCV-RNA, alanine aminotransferase > 1.5-fold upper limit of normal, abnormal liver histology, CD4 cell count > 250 × 106/l and HIV RNA < 10 000 copies/ml. Patients were assigned to INF (3 × 106 units three times/week) or PEG-IFN (100–150 μg/week) plus RBV (800–1200 mg/day). Duration of treatment was 48 weeks (only 24 weeks for HCV genotypes 2 or 3 and baseline HCV RNA < 800 000 IU/ml). The primary endpoint was a sustained virological response (SVR). Results: Ninety-five patients were randomized (43 INF + RBV, 52 PEG-INF + RBV), 68% males, 82% injecting drug users; 63% genotypes 1 or 4 and 36% genotypes 2 or 3; 62% fibrosis index grade ⩾2 and 30% bridging fibrosis/cirrhosis. SVR was significantly higher in the PEG-INF + RBV arm, 44% versus 21% (intent to treat; P = 0.017). Among patients with genotypes 1 or 4, SVR were 38% versus 7% (P = 0.007) and 53% versus 47% (P = 0.730) for genotypes 2 or 3. CD4 cell count but not its percentage dropped in both arms and HIV RNA viral load did not change from baseline. Side effects were very frequent in both arms leading to treatment discontinuation in 14 patients without statistical differences between arms (P = 0.565). Conclusion: PEG-INF + RBV was significantly more effective than INF + RBV for the treatment of chronic hepatitis C in HIV co-infected patients, mainly of genotype 1 or 4.

Increased risk of pre-eclampsia and fetal death in Hiv-infected pregnant women receiving highly active antiretroviral therapy

Background:Pre-eclampsia and/or fetal death have increased sharply in HIV-infected pregnant women receiving HAART. Methods:The occurrence of pre-eclampsia or fetal death was analysed in women who delivered after at least 22 weeks of gestation for all women (January 2001 until July 2003) and for HIV-infected women (November 1985 until July 2003). Results:In 2001, 2002 and 2003, the rates per 1000 deliveries of pre-eclampsia and fetal death, respectively, remained stable in all pregnant women at 25.4, 31.9 and 27.7 (P = 0.48) and 4.8, 5.8, and 5.0 (P = 0.89) (n = 8768). In 1985–2000 (n = 390) to 2001–2003 (n = 82), rates per 1000 deliveries in HIV-infected women rose from 0.0 to 109.8 (P < 0.001) for pre-eclampsia and from 7.7 to 61.0 (P < 0.001) for fetal death. In all pregnant women, factors associated with pre-eclampsia or fetal death were multiple gestation [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI), 2.3–5.6; P < 0.001], HIV infection (adjusted OR, 4.9; 95% CI, 2.4–10.1; P < 0.001), multiparity (adjusted OR, 0.76; 95% CI, 0.58–0.98; P = 0.040) and tobacco smoking (adjusted OR, 0.65; 95% CI, 0.46–0.90; P = 0.010). The use of HAART prior to pregnancy (adjusted OR, 5.6; 95% CI, 1.7–18.1; P = 0.004) and tobacco smoking (adjusted OR, 0.183; 95% CI, 0.054–0.627; P = 0.007) were risk factors in HIV-infected women. Conclusions:HIV infection treated with HAART prior to pregnancy was associated with a significantly higher risk for pre-eclampsia and fetal death.

Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area

Since the introduction of highly active antiretroviral therapy (HAART), the incidence of death in HIV‐infected patients has dramatically decreased, and causes of death other than those related to HIV infection have increased, although it is unclear how these parameters compare with those in the age‐matched general population living in the same geographical region.

A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression.

Background:Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression. Methods:We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure [“switching = failure” intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function. Results:Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval −2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group. Conclusions:In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

Clinical, virologic, and immunologic response to efavirenz-or protease inhibitor-based highly active antiretroviral therapy in a cohort of antiretroviral-naive patients with advanced HIV infection (EfaVIP 2 study).

Objective:To compare the clinical, immunologic, and virologic outcomes of efavirenz (EFV)-based versus protease inhibitor (PI)–based highly active antiretroviral therapy (HAART) in severely immunosuppressed HIV-1–infected patients. Design:Retrospective observational cohort study. Methods:Responses were analyzed according to the intent-to-treat principle among antiretroviral-naive patients with <100 CD4 cells/μL who started EFV (n = 92) or a PI (n = 218) plus 2 nucleoside reverse transcriptase inhibitors. The primary end point was time to treatment failure. Secondary end points were percentage of patients with a viral load <400 copies/mL, time to virologic failure, time to CD4 lymphocyte count >200 cells/μL, and incidence of opportunistic events or death. Results:The median baseline CD4 cell count and viral load were 34 cells/μL and 5.54 log10 copies/mL (EFV group) and 38 cells/μL and 5.40 log10 copies/mL (PI group). Time to treatment failure was shorter with a PI-based regimen than with an EFV-based regimen (adjusted relative hazard [RH] = 2.19, 95% confidence interval [CI]: 1.23–3.89). After 12 months of therapy, a significantly higher proportion of patients receiving EFV reached a viral load <400 copies/mL (69.4 vs. 45.1%; P < 0.05). The probability of virologic failure was higher with a PI than with EFV (adjusted HR = 2.52, 95% CI: 1.14–5.61; P = 0.024). There was no difference in time to CD4 cell count >200 cells/μL or in incidence of opportunistic events or death. Conclusion:In severely immunosuppressed, antiretroviral-naive, HIV-1–infected patients, treatment with an EFV-based regimen compared with a nonboosted PI-based regimen resulted in a superior virologic response with no difference in immunologic or clinical effectiveness.

Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction.

Objective:To assess the effects of initiating abacavir-containing therapy on plasma lipids and cardiovascular biomarkers. Design:Sub-study of the BICOMBO study in which participants were randomized to switch their nucleoside backbone to either abacavir/lamivudine or tenofovir/emtricitabine. Methods:We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), osteoprotegerin, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), selectin E and P, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients randomly switched to abacavir/lamivudine or tenofovir/emtricitabine with no history of cardiovascular disease, no prior abacavir or tenofovir use, and no virological failure or AIDS during follow-up. Results:Eighty (46 abacavir/lamivudine and 34 tenofovir/emtricitabine) patients were included. Baseline characteristics were similar between groups and between patients in the sub-study vs. those not. There were no significant differences in baseline lipids and markers between groups. Although total (6.5 vs. −6.7%, P < 0.0001) and low-density lipoprotein (LDL) (8.6 vs. −9.1%, P = 0.004) cholesterol increased significantly in the abacavir/lamivudine group relative to the tenofovir/emtricitabine group, we found no significant changes in the biomarkers: CRP (−3.9 vs. 0.0%), MCP-1 (5.9 vs. 4.0%), osteoprotegerin (5.1 vs. −2.8%), IL−6 (0.0 vs. 0.0%), IL-10 (0.0 vs. 0.0%), TNF-alpha (0.0 vs. 0.0%), ICAM-1 (6.6 vs. 5.2%), VCAM-1 (0.02 vs. −0.01%), selectin E (−0.4 vs. 7.8%), selectin P (4.6 vs. 12.6%), insulin (−2.5 vs. 8.8%), adiponectin (−2.2 vs. 15.4%), and D-dimer (0.0 vs. 0.0%) (P ≥ 0.12 for all comparisons). Conclusion:Abacavir/lamivudine increased total and LDL cholesterol compared with tenofovir/emtricitabine, but it did not cause inflammation, endothelial dysfunction, insulin resistance, or hypercoagulability in virologically suppressed HIV-infected patients.

Association of HIV infection with spontaneous and iatrogenic preterm delivery: effect of HAART.

Objectives:To assess the association between HIV infection and both spontaneous and iatrogenic preterm delivery (PTD), and to explore the impact of HAART on both entities. Methods:A matched retrospective cohort study was carried out on 517 HIV-infected pregnant women who consecutively attended a university referral hospital between 1986 and 2010. Two controls were assigned for each case. They were matched by ethnicity, smoking, maternal age and educational level. Exclusion criteria were multiple pregnancy and active injection drug use (IDU). PTD was defined as delivery less than 37.0 weeks. Spontaneous PTD included preterm premature rupture of membranes. Iatrogenic delivery was considered if medically indicated. Factors associated with PTD among HIV-infected women were analyzed by logistic regression. Results:A total of 1557 pregnant women were analyzed (519 HIV-infected and 1038 noninfected). The incidence of PTD was 19.7% in HIV-infected women and 8.5% in controls [odds ratio (OR) 2.6; 95% CI 1.9–3.6]. There was a significantly higher incidence of both spontaneous [adjusted OR (AOR) 2.1; 95% confidence interval (CI) 1.5–3.0] and iatrogenic prematurity (AOR 3.2; 95% CI 1.8–5.7). Iatrogenic PTD was significantly associated with the use of HAART during the second half of pregnancy, whereas spontaneous PTD was not related to HAART. Conclusion:There is a significant association of HIV infection with PTD, both spontaneous and iatrogenic PTD. HAART use was predominantly associated with iatrogenic PTD.

Decreased pregnancy rate after in-vitro fertilization in HIV-infected women receiving HAART.

A study on in-vitro fertilization (IVF) was conducted among HIV-infected women. In these patients, a reduced pregnancy rate after IVF was observed if the patients own oocytes were used. However, no significant reduction in the pregnancy rate was found if donated oocytes were used. The CD4 lymphocyte count was independently associated with ovarian resistance to hyperstimulation. Subclinical hypogonadism mediated by immunosuppression may explain these observations, suggesting the need to optimize the immunological status of the patient before considering assisted reproduction treatments.

Filgrastim to treat neutropenia and support myelosuppressive medication dosing in HIV infection

Background: Patients with HIV infection frequently experience disease or treatment‐related myelosuppression leading to neutropenia. Neutropenia often leads to dose‐reduction or discontinuation of important myelosuppressive therapy. Objective: To examine the efficacy and safety of filgrastim for reversing neutropenia and determine the effect of this on use of myelosuppressive medications. Design: Open‐label, non‐comparative, multicentre study in 200 HIV‐positive patients with neutropenia [absolute neutrophil count (ANC) < 1.0×109/l]. Filgrastim was started at 1 &mgr;g/kg/day subcutaneously for 28 days. This initial treatment phase was followed by a maintenance phase, using 300 &mgr;g on 1‐7 days/week. In both phases the dose of filgrastim was adjusted to achieve an ANC of 2‐5×109/l. Results: Filgrastim reversed neutropenia in 98% of patients (ANC ≥2×109/l), with a median time to reversal of 2 days (range 1‐16) and a median dose of 1 &mgr;g/kg/day (range 0.5‐10). Most patients (96%) achieved reversal of neutropenia with a filgrastim dose of ≤ 300 &mgr;g/day (≤1 vial/day). Normal ANCs were then maintained with a median of 1 &mgr;g/kg/day (range 0.22‐10.6) during the treatment phase and 3×300 &mgr;g vials/week (range 1‐7) during the maintenance phase. Ganciclovir, zidovudine, co‐trimoxazole and pyrimethamine were the drugs most frequently considered to be causing neutropenia, and 83% of patients received one or more of these in the study. Filgrastim allowed > 80% of patients to increase or maintain dose‐levels of these four medications or add them to their therapy. The number of these four medications received per patient increased by > 20% during filgrastim therapy. Filgrastim was well tolerated. CD4, CD8 and total lymphocyte counts all increased slightly, and there was no difference in HIV‐1 p24 antigen levels. Conclusion: Filgrastim rapidly reverses neutropenia and maintains normal ANC in patients with HIV infection. This allows greater use of myelosuppressive medications without the potentially life‐threatening complications of neutropenia.

Fertility assessment in non-infertile HIV-infected women and their partners

The objective of the study was to assess the fertility of non-infertile couples seeking pregnancy in whom the woman was HIV infected. Therefore, a cross-sectional study was conducted between January 1998 and March 2005. A standardized fertility assessment was performed in all the included couples. A total of 130 women and 121 men were evaluated. Their median age was 34 years (range 22-43). Only 7.2% of the women were severely immunocompromised. The majority of women had regular cycles. Only one woman had an active sexually transmitted disease at the time of evaluation. A tubal occlusion on hysterosalpingogram was present in 27.8% of the women with no proven fertility. In 50.5% of the women, hepatitis C virus co-infection was present. One-third of the male partners (38/121) was infected with HIV. Abnormal semen parameters were observed in 83.4% of HIV-infected and 41.7% of HIV-uninfected partners (OR = 7; 95% CI = 2.1-23). It is concluded that the great majority of the HIV-infected women seeking pregnancy had a good infection status. Because in many of the couples, the women presented unexplained tubal occlusions and the men presented semen alterations, a hysterosalpingography and semen analysis should be part of the preconceptional investigations.