Switching to emtricitabine, tenofovir and rilpivirine as single tablet regimen in virologically suppressed HIV-1-infected patients: a cohort study.

OBJECTIVES: Emtricitabine/tenofovir/rilpivirine as a single-tablet regimen (STR) is widely used without licence in treatment-experienced patients. The purpose of this retrospective observational study was to assess viral suppression of ART-experienced patients switching to STR. METHODS: We assessed 131 pretreated patients switching to STR with HIV RNA <400 HIV-1 RNA copies/mL. The primary outcome measure was the proportion of patients at week 24 with HIV RNA <40 copies/mL. RESULTS: By week 24, eight patients had stopped STR: four because of adverse events and four for other reasons. Three virological failures were observed; among these, at least one patient developed cross-resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), in particular with the E138K pattern. In intent-to-treat analysis, 92% of participants (120 of 131) achieved HIV RNA <40 copies/mL. Only grade 1 to 2 adverse events were observed, mainly consisting of increased liver enzymes (n=33). Systemic exposure to rilpivirine was above the usually observed steady-state levels for the 18 measurements assessed. CONCLUSIONS: Efficacy and tolerability are similar to those in treatment-naïve patients.

[Reproductive options for people living with HIV: 2013 guidelines from the French expert working group]. / Désir d'enfant chez les personnes vivant avec le VIH : nouvelles recommandations 2013 du groupe d'experts français.

The desire for children is a legitimate aspiration that should be part of multidisciplinary care for all men, women or couples living with HIV. The use of effective antiretroviral therapy has revolutionized the prevention of sexual, as well as mother-to-child HIV transmission. When the HIV plasma viral load is undetectable on long-term antiretroviral therapy, the risk of mother-to-child transmission is <1% and the risk of heterosexual HIV transmission without condom use in a stable relationship is very low (estimated at less than 1/10,000) in the absence of inflammation of the genital tract. In a man with a long-term undetectable viral load, viral shedding in semen is uncommon, but may occur persistently or intermittently. The same appears true of viral shedding in the vaginal tract of women. Reproductive options are: natural conception, self-insemination when the woman is HIV-infected, assisted reproduction. Natural conception is now considered to be an acceptable option when the conditions are met, after exploring four aspects: (1) virological (viral load undetectable sustained for at least 6 months on therapy), (2) genital (absence of genital infections or lesions), (3) fertility (after appropriate evaluation) and (4) detecting the ovulation period to limit intercourse without condoms. Assisted reproduction has two objectives in the context of HIV, to allow the couple to conceive without abandoning condom use and/or to treat infertility.

[HIV and pregnancy: 2013 guidelines from the French expert working group]. / Infection par le VIH et grossesse: nouvelles recommandations 2013 du groupe d'experts français.

With effective antiretroviral therapy, the risk of mother to child transmission (MTCT) is now under 1%. The 2013 French guidelines emphasize early antiretroviral lifelong antiretroviral therapy. Thus, the current trend for women living with HIV is to take antiretroviral therapy before, during and after their pregnancies. A major issue today is the choice of antiretroviral drugs, to maximize the benefits and minimize the risks of fetal exposure. This requires interdisciplinary care. The use of effective therapies permits gradual but profound changes in obstetric practice. When maternal plasma viral load is controlled (<50 copies/ml), obstetrical care can be more similar to standards in HIV-negative women. Prophylactic cesarean section is recommended when the viral load in late pregnancy is above 400 copies/mL. Intravenous zidovudine during labor is recommended only if the last maternal viral load is>400 copies/mL or in case of complications such as preterm delivery, bleeding or chorio-amnionitis during labor. In case of premature rupture of membranes before 34 weeks, a multidisciplinary decision should be made, based on gestational age and control of maternal viral load; if the woman is under antiretroviral therapy and especially if her viral load is undetectable, steroids and antibiotics should be offered and pregnancy can be continued except in case of signs or symptoms of chorio-amnionitis. Breastfeeding is not recommended in women living with HIV in France, as in industrialized countries. Prophylaxis in the newborn is usually zidovudine for 1 month. In case of significant exposure to HIV perinatally, in particular when, maternal viral load is>1000 copies/mL, prophylactic combination therapy is recommended. Monitoring of the child is necessary to determine whether or not it is free of HIV infection and to monitor possible adverse effects of perinatal exposure to antiretroviral drugs.

[Assisted reproductive technique for an opiates dependant couple]. / Assistance médicale à la procréation chez un couple dépendant aux opiacés.

The aim of our network "Motherhood and Addiction Alsace" is to take care of opiates addicted pregnant women in order to permit the birth of a healthy child, raised by stabilized parents both on drug use and psychosocial status. A couple, both on methadone treatment, with chronic hepatitis for the husband had access to an in vitro fertilization program thanks to the network care. The difficulties on the path to parenthood, the adequate use of painkillers, neonatal care and the use of a coordinated action of all health professionals are discussed.

[Inadequate vaccination coverage in a French cohort of HIV positive patients]. / Insuffisance de couverture vaccinale d'une cohorte française de patients séropositifs VIH.

INTRODUCTION: HIV patients have a high rate of infectious complications. Vaccination, though less efficient in case of severe immunosuppression, can prevent some of these infections. Since 2006, new vaccine recommendations have been elaborated in France. We studied the vaccine status of HIV+ patients for influenza, Streptococcus pneumoniae, tetanus, and hepatitis A and B among an alsatian HIV+ population. PATIENTS AND METHODS: From August 20, 2007 to September 15, 2007, HIV patients of the Alsace HIV center (COREVIH) were included in a prospective study, screening demographic, medical, immunovirological, and vaccination data. RESULTS: Three hundred and thirty-one patients were included, 49% of whom were asymptomatic, 29% symptomatic without AIDS, 18% at AIDS stage, and no documentation for 4%. Seventy-one patients (21.4%) were vaccinated against influenza, 11 (3.3%) against Streptococcus pneumoniae, 34 against HAV (only 16.3% of patients with a negative test before), 120 against HBV (60% of patients with no serological markers before), and 186 (56.2%) against tetanus. The most frequent reasons for non-vaccination were non-proposal by physicians, lack of expected effectiveness, and fear of an immunovirological adverse effect. CONCLUSION: Vaccination coverage for recommended vaccines of HIV infected people remains at a low level and appears sometimes inferior to the rates reached among the general French population. It is necessary to inform prescribers and HIV positive patients about the interest of vaccination.

[Alterations of ovarian reserve tests in Human Immunodeficiency Virus (HIV)-infected women]. / Altérations des marqueurs de la réserve ovarienne chez les femmes infectées par le virus de l'immunodéficience humaine.

OBJECTIVES: Little is known about the impact of highly active antiretroviral therapy or HIV infection itself on the ovarian function. The aim of this study was to evaluate ovarian function in HIV-infected women in comparison with normal values from non-HIV infected women. PATIENTS AND METHODS: This is a prospective pilot study using markers of ovarian function: the antral follicular count (AFC) defined between cycle days 7 and 10 and follicle-stimulating hormone (FSH), inhibin B and antimüllerian hormone (AMH) for early follicular phase hormonal assessments. A descriptive analysis according to age was performed. RESULTS: Results from 78 HIV positive women are presented. AFC shows a high rate of abnormal values (63 %) occurring surprisingly early. The hormonal markers are concordant with a 36, 57 and 23 % abnormal rate for FSH, inhibin B and AMH respectively. DISCUSSION AND CONCLUSION: In our series, HIV seropositivity was associated with stigmas of premature ovarian insufficiency. This may explain impaired fertility but also suggests premature menopause in this population that should therefore be monitored early for such changes.

[The desire to become a parent when infected with human immunodeficiency virus, hepatitis C virus or hepatitis B virus]. / Désir d'enfant et infections virales: hépatites C et B et virus de l'immunodéficience humaine.

The French law (arrêté du 10 mai 2001) allows Assisted Reproductive Techniques (ART) in case of infection with human immunodeficiency virus, hepatitis C virus or hepatitis B virus. Our six years' experience is positive even if pluridisciplinary care needs specific equipment and human forces. Couples express high motivation. The wish to become a parent leads to a better care of the infection. ART results are excellent in case of male contamination, not as good when the female partner is infected but still encouraging. No contamination of the partner or the offspring occurred after ART. Data are already collected in France in this context. A European register should be constituted in an early future.

Influence of gender and HIV transmission group on initial highly active antiretroviral therapy prescription and treatment response.

BACKGROUND: The literature contains conflicting findings on the influence of gender and HIV transmission group on the initial prescription of highly active antiretroviral therapy (HAART) and its biological and clinical efficacy. METHODS: We conducted a cohort study involving 62 French hospitals. We used Cox proportional hazards models to examine whether gender and HIV transmission group influenced the timing of elective HAART initiation, and the clinical and biological response to treatment. RESULTS: We studied 5735 patients enrolled between January 1997 and December 2001 who did not start HAART or develop a stage C HIV-related event during the first 3 months after inclusion. In multivariate analysis, no gender differences were found in the interval between enrollment in the database and HAART initiation, but this interval was shorter in homosexual patients than in other transmission groups; CD4 cell counts at treatment initiation were also higher in the homosexual group. The immunovirological response to treatment did not differ according to gender, but was better in homosexual patients than in patients in other categories. Injecting drug users had the weakest immunovirological responses. Clinical outcome was not related to gender or to HIV transmission group. CONCLUSIONS: The interval between diagnosis of HIV-1 infection and elective HAART initiation was not influenced by gender. However, homosexual patients had higher CD4 cell counts than other patients at treatment initiation, and also had better immunovirological responses.

[Hepatitis A seroprevalence in HIV-infected patients]. / Séroprévalence de l'hépatite A chez des patients infectés par le VIH.

OBJECTIVE: The authors had for aim to prospectively study the hepatitis A seroprevalence of an HIV-infected population, followed-up in an outpatient clinic (CISIH Strasbourg). DESIGN: Blood tests were performed on all patients from September 2003 to March 2004 to screen for hepatitis A (total antibodies with Elisa). RESULTS: The overall seroprevalence was 219/514 (56.6%), similar in male and female patients. It increased with age, especially in European patients (P = 0.003). The seroprevalence was lower in European subjects: 46.3% (while it reached 100% in sub-Saharan Africans), the prevalence was similar whatever the HIV risk group (46% in homosexual as well as in heterosexual patients, 44% in intravenous drug users). Hepatitis B or C co-infection did not increase the seroprevalence of hepatitis A. The hepatitis A seroprevalence was similar in various CD4 T cell count categories. CONCLUSIONS: Our results stress the utility of hepatitis A serology in HIV-infected patients (more than 50% of European patients are non immune), and the importance of assessing hepatitis A vaccination.

[Structured therapeutic interruption in patients infected with HIV-1 experiencing a block in their antiretroviral treatment: preliminary results]. / Interruption thérapeutique programmée chez des patients infectés par le VIH-1 en échec d'un traitement antirétroviral: résultats préliminaires.

Structured therapeutic interruption (STI) has been offered to HIV-1 infected patients with virological failure (viral load > 1500 copies/mL) of potent antiretroviral therapy (ART) (three or four drugs for at least one year). CD4 lymphocyte count, HIV-1 viral load, clinical status, were assessed every month during STI and after ART reintroduction. Genotype analysis by plasma virus sequencing was done before and after treatment interruption. The results of 14 patients who resumed ART for at least two months are presented. Median duration of STI was 7.5 months (range: 2-13 months). Median CD4 count was low (45/mm3) when treatment was stopped, and decreased during STI (-37/mm3 after six months). Several patients exhibited important CD4 diminutions. Viral load slightly increased (+0.83 log at M6). Few clinical events occurred: one: severe HIV-related prurigo and one CMV viremia. Reversion of resistance mutations was only seen in 2/13 (15: 4%) patients (who had previously a major CD4 deficiency, and a long treatment history), a partial reversion occurred in 5/13 (38.5%) subjects, and the mutations didn't change in the other cases (genotyping non interpretable in the last patient). ART reintroduction induced a good immune response: CD4/mm3 after six months, with significant increases in 10/14 subjects. There was an initial viral response (median viral load: -2.34 log at M1), but a quick rebound most often occurred. However, viral load remained < 50 copies/mL in four patients. In conclusion, a rapid and important decline in CD4 cell count can occur when treatment is discontinued, in patients with virological failure of ART, but the clinical risk appears to be limited. Treatment re-initiation induces a good response, but virologically transient in most cases. Patients with a shift to wild-type virus seem to have a better response.

Efavirenz as a substitute for protease inhibitors in HIV-1-infected patients with undetectable plasma viral load on HAART: a median follow-up of 64 weeks.

We investigated, in a prospective cohort follow-up study, whether substituting efavirenz (EFV) for protease inhibitors (PIs) could be safe in HIV-infected patients with optimal viral suppression achieved on PI-containing regimens. In patients with undetectable plasma viral load (pVL) <50 copies/ml who were naive to therapy with nonnucleoside reverse transcriptase inhibitors (NNRTIs), PIs were replaced by EFV whereas associated nucleoside analogs (NAs) were retained. 62 patients were enrolled. Median follow-up on EFV was 64 weeks (2-88 weeks). Side effects due to EFV occurred in 48 patients. Two patients experienced a high level viral rebound due to diminished compliance; 55 (88.7%) maintained a pVL <50 copies/ml; 3 showed one episode of viremia (52-89 copies/ml); 2 stopped EFV before any VL control. Mean CD4 cell count did not change significantly. One AIDS patient experienced a single cutaneous recurrence of Kaposi's sarcoma after 40 weeks on EFV. Replacing PI with EFV in patients with optimal pVL suppression appears to be safe both virologically and immunologically.

[Multicenter study of intrafamilial transmission of hepatitis C virus in human immunodeficiency virus infection]. / Etude multicentrique de la transmission intra-familiale du virus de l'hépatite C dans le contexte de l'infection par le virus de l'immunodéficience humaine.

OBJECTIVE: Intrafamilial transmission of hepatitis C virus in human immunodeficiency virus and hepatitis C virus co-infections is not well documented. This cross-sectional study evaluated the transmission of hepatitis C virus in the sexual partners of hepatitis C virus and human immunodeficiency virus co-infected patients. METHODS: Hemophiliacs and transfused hepatitis C virus and human immunodeficiency virus co-infected patients who were being seen in three French university hospitals, and their sexual partners were studied by a face-to-face interview using an epidemiological questionnaire and by biological tests: antibodies against hepatitis C virus, hepatitis C virus RNA, and ALT activity. RESULT: Fifty-two subjects were included: 26 cases and their 26 sexual partners. Three sexual partners (11.5 %) had anti-hepatitis C virus antibodies, two of whom had an undetermined RIBA test. All three had a risk factor for hepatitis C virus infection (transfusion, intra-muscular injections with re-usable needles). Two of these three partners were also human immunodeficiency virus antibody positive. Hepatitis C virus RNA was negative in all sexual partners. CONCLUSION: This study provides evidence of a low prevalence of anti-hepatitis C virus antibodies in sexual partners of hepatitis C virus and human immunodeficiency virus co-infected patients. It does not support intra-familial transmission of hepatitis C virus.

Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study.

BACKGROUND: Fat distribution abnormalities have been reported in patients treated with various antiretroviral drug regimens. The LIPOCO study is an ongoing observational study of unselected HIV-infected patients which aims to better characterize such disorders and their metabolic correlations. METHODS: Cross-sectional analysis of data collected at baseline in the first 154 male patients included. Investigators divided patients into four predetermined clinical categories of fat distribution: lipoatrophy, obesity, mixed condition and normal. Body composition (tetrapolar bioelectrical impedance analysis and skinfold thickness), fat distribution [computed tomography (CT) scan], plasma glucose and insulin concentrations both fasting and during an oral glucose tolerance test and endocrine and lipid profile were measured and compared between the four groups. RESULTS: Patients in the lipoatrophy group had significantly decreased abdominal and mid-thigh subcutaneous fat area values and elevated levels of plasma triglycerides. Patients in the obese and mixed groups had significantly increased intra-abdominal fat area values and elevated levels of plasma insulin and C-peptide. The CT scans identified some patients with isolated subcutaneous fat accumulation but no other alterations in fat distribution and no insulin resistance. Visceral adipose tissue measured by CT scan was positively correlated with fasting insulin and the sum of insulin levels (P < 0.0001). Fasting insulin as well as the sum of insulin levels were negatively correlated with the delta HIV-RNA (log(10)). In a multivariate logistic regression model, the use of stavudine significantly correlated with fat wasting in both nucleoside reverse transcriptase inhibitor and protease inhibitor groups: odds ratio (OR), 413 [95% confidence interval (CI), 5.2-999; P = 0.0068] and OR, 2.08 (95% CI, 0.92-7.0; P = 0.058) respectively, when compared with the use of zidovudine. Neither lamivudine or didanosine use, nor the use of protease inhibitors were significantly associated with fat distribution abnormalities or fat wasting. CONCLUSIONS: These preliminary results suggest that three major types of fat distribution abnormalities may occur in isolation or in association in HIV-infected patients undergoing active antiretroviral therapy: a fat depletion or 'lipoatrophy' syndrome which might be related to the use of stavudine; a mixed or fat redistribution syndrome related to an unusual side-product of effective virus control; and a subcutaneous adiposity syndrome reflecting increase in caloric intake.

[Emergence of resistant hepatitis B virus strains during long-term lamivudine therapy in human immunodeficiency virus co-infected patients]. / Emergence de souches résistantes de virus de l'hépatite B, sous traitement prolongé par lamivudine, chez des malades co-infectés par le virus de l'immunodéficience humaine.

Seven patients co-infected with hepatitis B virus (HBsAg and HBeAg carriers, quantifiable HBV DNA with the bDNA technic) and human immunodeficiency virus received a triple antiretroviral combination therapy, including lamivudine (150 mg twice a day). Hepatitis B viral load rapidly became undetectable in 6/7 patients. It remained below the level of detection in 2 subjects, after 20 and 22 months of treatment, with one of them achieving HBeAg/anti-HBe seroconversion. However, in the other 4 individuals, hepatitis B viremia increased again after 8 to 16 months of lamivudine-containing regimen. The last patient was a non-responder. The 4 relapsers developed a double mutation Leu(528) for Met(528) and Met(552) for Val(552), on hepatitis B virus polymerase, either concomitant (M8 and M16) with a hepatitis B virus DNA increase, or 2 months earlier (M10 and M12). The high frequency of hepatitis B virus resistance to lamivudine emphasizes the necessity of identifying more effective strategies, such as double combination therapies.

Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load.

Preventing hepatitis B by vaccination is essential in HIV-infected patients (higher progression rate of HBV infection to chronicity, lower rate of serum HBe Ag loss). However, it has been shown a decreased anti-HBs response in these individuals after a standard vaccination (3 doses of 20 micrograms). Thus, we tested the hypothesis that doubling the number of hepatitis B vaccine injections might increase anti-HBs response rate. HIV-infected patients with CD4 > 200/microliter, who were on stable antiretroviral treatment, as well as seronegative for HBV markers, and who have never been vaccinated against HBV, were given 3 intramuscular injections of Genhevac B 20 micrograms at 1 month intervals. Initial non responders were given 3 additional monthly injections. Anti-HBs titer was followed. We also evaluated the effects on HIV-1 viral load. Twenty patients with a median CD4 cell count of 470/microliter were enrolled. The response rate after three 20 micrograms injections was 55% (11/20), lower in individuals with CD4 between 200 and 500/microliter (4/12 = 33.3%), compared to patients with CD4 above 500/microliter (7/8 = 87.5%, P = 0.02). Among 9 initial non-responders, only 2 did not respond to 3 additional doses; thus, the overall response rate was 90% (18/20). Geometric mean titers of anti-HBs were 133 IU/l and 77.5 IU/l, after 3 and 6 Genhevac doses, respectively (P = 0.38). One year later, only 10/17 (58.8%) patients had protective anti-HBs. Five patients experienced a significant viral load increase, transient in 3 cases. These preliminary results suggest that doubling the number of hepatitis B vaccinations in HIV-infected patients might significantly improve anti-HBs response rate; however, close monitoring of anti-HBs is necessary because of its short-lived persistence. The effects on HIV-1 viral load are limited.

A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy.

OBJECTIVE: To compare body composition, body fat distribution and insulin secretion in patients taking nucleoside reverse transcriptase inhibitor (NRTI) therapy. DESIGN AND SETTING: Cross-sectional study in three French AIDS clinical centres. PATIENTS: Forty-three HIV-infected patients on long-term NRTI therapy including stavudine (n = 27) or zidovudine (n = 16) and 15 therapy-naive HIV-infected patients (control group). MAIN OUTCOME MEASURES: Fat wasting was assessed by physical examination and body composition by bioelectrical impedance. Regional fat distribution was estimated using caliper measurements of skinfold thickness at four sites and evaluated by computed tomography at abdominal and mid-thigh level. Fasting glucose, insulin, C-peptide, triglyceride, cholesterol, free fatty acid, testosterone, follicle stimulating hormone, luteinizing hormone, cortisol levels, CD4 cell count and HIV viral load were determined. Daily total caloric and nutrient intake were evaluated. RESULTS: The zidovudine group and the control group had similar body composition and regional fat distribution. Stavudine therapy was associated with a significantly lower percentage of body fat (12.9% versus 15.2% in the zidovudine group; P < 0.05), markedly decreased subcutaneous to visceral fat ratio (0.90 +/- 0.63 versus 1.92 +/- 1.34, P < 0.01) and higher mean intake of fat and cholesterol (P < 0.01). Fasting plasma glucose, insulin and C-peptide levels were similar among the three groups. Triglyceride levels were significantly higher in the stavudine group than in the controls (P < 0.05), but did not differ between the stavudine and the zidovudine group or between the zidovudine and the control group. Free fatty acids tended to be higher in the stavudine group but the difference did not reach statistical significance. Lipodystrophy was observed clinically in 17 (63%) patients taking stavudine, and in three (18.75%) patients taking zidovudine after a median time of 14 months. The relative risk of developing fat wasting was 1.95 in the stavudine group as compared with the zidovudine group (95% confidence interval, 1.18-3.22). Five out of 12 patients had a major or mild improvement in their lipodystrophy after stavudine was discontinued. CONCLUSION: Lipodystrophy may be related to long-term NRTI therapy, particularly that including stavudine.

Expression and targeting to the plasma membrane of xClC-K, a chloride channel specifically expressed in distinct tubule segments of Xenopus laevis kidney.

ClC-K channels are Cl- channels specifically expressed in vertebrate kidneys. Although their heterologous functional expression is still controversial, indirect evidence points to them as major factors involved in Cl- reabsorption in the nephron. We cloned xClC-K, an amphibian (Xenopus) homologue of mammalian ClC-K. The cDNA encodes a 77 kDa protein presenting 62% similarity with human ClC-Kb. The protein is monoglycosylated and is expressed primarily in the Xenopus kidney. It is localized in the basolateral membranes of proximal convoluted tubules of the nephron and in the apical region of the diluting segments. Heterologous expression of xClC-K in HEK-293 cells showed that the full-length protein is glycosylated and targeted to the cell membrane, but no associated Cl- current could be observed with the patch-clamp recording technique. N-glycosylation of both the native kidney channel and the recombinant protein expressed in HEK-293 conferred on them anomalous behaviour in denaturing PAGE, which is indicative of strong interactions at the extracellular side of the plasma membrane. The expression of ClC-K channels in both mesonephric and metanephric kidneys will permit further comparative physiological studies of Cl- permeabilities at the molecular level.