Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).

OBJECTIVES: Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS: We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS: Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS: LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.

[Pregnancy associated Plasmodium falciparum malaria discovered fortuitously: report of two cases]. / Découverte fortuite de paludisme àPlasmodium falciparum au cours de la grossesse : à propos de deux cas.

We report two cases of pregnancy-associated Plasmodium falciparum malaria discovered fortuitously. These two women were born in Africa and their last visit in an endemic area was more than one year before. It is well known that pregnancy is one of major risks of late onset of P. falciparum malaria. In the two cases reported in this study, clinical signs of malaria were not specific and we will describe the interest to detect more systematically pregnant African women, first arrival immigrants.

[Use of enfurvitide in pregnancy in HIV positive women in seven cases]. / Utilisation de l'enfuvirtide chez la femme enceinte séropositive VIH, à propos de sept cas.

OBJECTIVE: With a panel of more than 22 drugs, the treatment of HIV subjects is nowadays quite easier. But due to the number of multiparus women often harbouring a multidrug resistant virus, or seen late in pregnancy or inobservant, taking care of these pregnancies remains difficult. The use of enfuvirtide seems quite interesting for these situations. PATIENTS AND METHODS: In a retrospective study, we have focused our work on the consequences of enfuvirtide used in seven pregnancies, paying particular attention to efficacy, pharmacokinetics and tolerance. RESULTS: The use of enfuvirtide during 30 days in average seems safe and the tolerance was satisfactory in all seven cases. All infants are seronegative without abnormalities. The dosages in umbilical cord were negative. Five women experienced an elective caesarean, one had caesarean section in emergency, and one had a vaginal delivery. DISCUSSION AND CONCLUSION: The 23 cases published in the English literature indicate the interest of enfuvirtide use in these difficult situations. Indeed, enfuvirtide is injectable, favouring the adherence; it has a good tolerance, a quick efficacy and no placental transfer. Evidently, enfuvirtide is always prescribed in association.

Factors related to medical appointment attendance after childbirth among HIV-infected women in the Paris region.

This study examined factors related to medical appointment attendance after childbirth among HIV-infected women in the Paris region. We hypothesized that despite regular utilization of prenatal care, many women may not attend medical appointments after delivery for their own HIV infection. This was an observational cohort study of HIV-seropositive women delivering in four Paris hospitals in 2001. Follow-up attendance through 24 months after delivery was defined as 'regular' for women who had > or =4 HIV visits during the period, 'irregular' for <4 visits in the 24-months period and/or a gap between two visits >12 months, and 'no attendance' when < or =1 visit in the 2-year period. Of 169 women enrolled, 125 (75%) had regular attendance, 24 (14%) had irregular attendance, and 18 (11%) had no attendance. Multivariate analysis found the greater number of HIV visits during pregnancy and the prescription of combination therapy (versus zidovudine monotherapy) during pregnancy to be significantly related to regular attendance. Of the 18 women who had no attendance, 8 women (47%) continued to attend regular paediatric appointments with their infants during the 24-month period. Scheduling more frequent HIV visits during pregnancy may establish a pattern that will improve attendance during the post-partum period. In addition, increased communication between the health care providers of the mother and child may increase appointment attendance following delivery.

[Efavirenz (Sustiva) in pregnancy: a study about 12 HIV patients]. / Grossesse sous efavirenz (Sustiva): à propos de 12 cas de patientes positives pour le VIH.

OBJECTIVE: In developed countries, where the mother-to-child transmission rate of HIV is low (1 to 1,5%), a major medical concern is the safety of new therapies during pregnancy. Teratogenicity has been described with an NNRTI, efavirenz (Sustiva), in animal model, regarding neural tube defects. PATIENTS AND METHODS: We have made a retrospective study of pregnancies starting with efavirenz with a special focus on foetal and infant abnormalities. RESULTS: Three abnormalities were notified no one linked to a neural tube defect. DISCUSSION AND CONCLUSION: In the English literature published, although the prevalence of abnormalities in human is low (1,7%) during pregnancy, due to the potent teratogenicity, efavirenz is contraindicated in the first trimester and should be used with caution in women of childbearing potential.

Intensification of stable background therapy with abacavir in antiretroviral therapy experienced patients: 48-week data from a randomized, double-blind trial.

OBJECTIVES: To evaluate antiretroviral efficacy of abacavir (ABC) in antiretroviral-experienced patients, by intensifying current antiretroviral therapy (CART) in patients with stable, detectable plasma HIV-1 RNA. METHODS: Thirty-two European centres recruited HIV-1 positive patients with < or = 36 months of CART experience. Patients were randomized to receive either ABC (300 mg twice daily) plus CART (ABC + CART) or ABC placebo plus CART (CART). We assessed efficacy as measured by plasma HIV-1 RNA and CD4+ cell counts and safety at baseline, weeks 2, 4 and every 4 weeks thereafter until week 48. Protocol-defined criteria enabled patients to switch to open-label ABC from week 8 onwards. RESULTS: Ninety-two patients with a median plasma of 3.66 log10 HIV-1 RNA copies/mL and a median CD4+ cell count of 408 cells/microL were randomized to ABC + CART and 93 patients with a median plasma of 3.52 log10 HIV-1 RNA copies/mL and a median CD4+ cell count of 411 cells/microL were randomized to CART. From weeks 8-48, 11 (12%) patients in the ABC + CART group and 34 (37%) patients in the CART group switched to open-label ABC. At week 48, significantly more patients on ABC + CART (23/92, 25%) than on CART (5/93, 5%) had plasma < or =400 HIV-1 RNA copies/mL (P < 0.001, intent-to-treat switch = failure population). Neither duration of previous nucleoside reverse transcriptase inhibitor treatment (up to 18 months) nor prior lamivudine therapy affected ABC efficacy. In the ABC + CART group, 16/25 (64%) patients with the M184V mutation at baseline had < or = 400 copies/mL or a decrease > or = 1 log10 copies/mL at week 16. More patients (19/46, 41%) with baseline viral load < or = 5000 copies/mL had plasma < 400 HIV-1 RNA copies/mL at 48 weeks than those > 5000 copies/mL (4/44, 9%). CD4+ cell counts increased by 102 cells/microL and 57 cells/microL at week 48 for the ABC + CART and CART groups, respectively (intent-to-treat, switch included). ABC addition had minimal impact on the CART safety profile. CONCLUSIONS: ABC intensification, in CART-experienced patients with low viral loads and limited reverse transcriptase mutations, most of whom had previously been on double-therapy, resulted in a significant and durable plasma HIV-1 reduction and concomitant increase in CD4+ cell count. The presence of M184V at baseline had minimal impact on the efficacy of ABC.

The role of abacavir (ABC, 1592) in antiretroviral therapy-experienced patients: results from a randomized, double-blind, trial. CNA3002 European Study Team.

OBJECTIVE: To compare the antiviral activity of abacavir (ABC) with stable background therapy (SBG) and SBG alone in antiretroviral therapy-experienced subjects as demonstrated by the proportion of subjects with plasma HIV-1 RNA < or = 400 copies/ml, plasma HIV-1 RNA and CD4 cell count profiles, and safety and tolerance of the two regimens over 16 weeks. DESIGN: One-hundred and eighty-five HIV-1 infected adults, with CD4 cell counts > or = 100 x 10(6)/l and plasma HIV-1 RNA of 400-50,000 copies/ml and who had received SBG therapy for at least 12 weeks, were randomized to receive ABC (300 mg twice daily) or placebo in a double blind, multi-centre study. METHODS: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4 cell counts. Genotypic and phenotypic resistance was determined at baseline and week 16. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: At week 16 significantly more subjects receiving ABC + SBG had plasma HIV-1 RNA < or = 400 copies/ml (36/92, 39%) than subjects receiving SBG alone (7/93, 8%; P < 0.001). A similar response was observed in both the lamivudine naive and lamivudine-experienced subjects. The presence of the M184V mutation did not preclude an antiviral response to ABC; 73% of subjects with the M184V mutation alone experienced a > or = 1.0 log10 copies/ml reduction in plasma HIV-1 RNA or had a value of < or = 400 copies/ml by week 16. CONCLUSIONS: ABC was generally well tolerated and exerted significant antiviral effect when added to combination antiretroviral therapy over 16 weeks.

Plasma cytomegalovirus DNA, pp65 antigenaemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy.

OBJECTIVE: To study the natural history and the current risk factors for cytomegalovirus (CMV) disease in the context of highly active antiretroviral therapy (HAART). SETTING: Prospective multicentre cohort in 15 university hospitals in France. METHODS: A group of 198 patients with CD4 cell count < 100 x 10(6) cells/l (or < 200 x 10(6) cells/l under HAART for at least 2 months), no previous CMV disease and CMV-positive serology were followed every 4 months clinically and for virological testing including HIV RNA and CMV blood markers (culture, pp65 antigenaemia, plasma CMV DNA and CMV late mRNA by the polymerase chain reaction). RESULTS: At inclusion, median CD4 was 77 x 10(6) cells/l (0-308) and 85% of the patients received protease inhibitors. The percentage of patients receiving HAART reached 99% at 12 months. After a follow-up of 23.6 months, the incidence of CMV disease was 3.2/100 patient-years [95% confidence interval (CI) 1.3-5.0]. In univariate Cox models, all the CMV markers, a CD4 cell count remaining < 75 x 10(6) cells/l and an HIV viral load > 100,000 copies/ml were predictive for CMV disease. The hazard ratios for CMV disease were 11 for blood culture; 14 and 70 for pp65 antigenaemia of > or = 1 and > or = 100 nuclei/200,000 cells, respectively; 35 for plasma CMV DNA; 6 for CMV mRNA; 29 for CD4 < 75 x 10(6) cells/l; and 12 for HIV RNA > 100,000 copies/ml. In a stepwise multivariate analysis, only three covariates were independently associated with the occurrence of a disease: plasma CMV DNA, pp65 antigenaemia > or = 100 nuclei/200,000 cells and a CD4 count < 75 x 10(6) cells/l. CONCLUSION: CMV blood markers and CD4 count < 75 x 10(6) cells/l remain risk factors for CMV disease in patients receiving HAART. Analysis of plasma CMV DNA by the polymerase chain reaction is a reproducible and standardized tool that could be used as a decision marker for initiating CMV pre-emptive therapy.

Phylogenetic analyses indicate an atypical nurse-to-patient transmission of human immunodeficiency virus type 1.

A human immunodeficiency virus (HIV)-negative patient with no risk factor experienced HIV type 1 (HIV-1) primary infection 4 weeks after being hospitalized for surgery. Among the medical staff, only two night shift nurses were identified as HIV-1 seropositive. No exposure to blood was evidenced. To test the hypothesis of a possible nurse-to-patient transmission, phylogenetic analyses were conducted using two HIV-1 genomic regions (pol reverse transcriptase [RT] and env C2C4), each compared with reference strains and large local control sets (57 RT and 41 C2C4 local controls). Extensive analyses using multiple methodologies allowed us to test the robustness of phylogeny inference and to assess transmission hypotheses. Results allow us to unambiguously exclude one HIV-positive nurse and strongly suggest the other HIV-positive nurse as the source of infection of the patient.

[Unusual vascular lesions in the course of a colonic leishmaniasis in an HIV positive patient]. / Lésions vasculaires inhabituelles au cours d'une leishmanoise colique chez un patient VIH poistif.

Patients with acquired immunodeficiency syndrome are often susceptible to atypical dissemination of visceral leishmaniasis. Digestive localizations seem to be relatively frequent. Colonic localizations reported in the literature are endoscopically normal or show superficial mucosal lesions. We describe an original case of leishmaniasis associated with a colonic pseudotumoral stenosis with perforated ulcer penetrating in the mesocolon. Striking inflammation of mesenteric blood vessels, even far from the ulcer, suggested an ischemic mechanism for the colonic stenosis. These findings raise the hypothesis that vasculitis is secondary to mucosal parasitic infection.

[Fibrosing cholestatic hepatitis by B virus reactivation in AIDS]. / Hépatite cholestatique et fibrosante par réactivation virale B au cours du SIDA.

We report an Hepatitis B Virus reactivation, in a patient with an end-stage Human Immunodeficiency Virus infection who developed a rapidly progressive liver failure in four months. The main histological features include ballooning of hepatocytes and ground glass transformation, without significant inflammation. Immunohistochemical staining showed a high expression of viral antigens. This case can be related to "Fibrosing Cholestatic Hepatitis", first described after liver transplantation for cirrhosis B. The mechanism of hepatocellular damage is likely to be a direct cytotoxicity of hepatitis B virus.

[Prevalence of Clostridium difficile and toxin A in feces of HIV infected patients]. / Prévalence de Clostridium difficile et de la toxine A dans les selles de patients VIH positifs.

Patients with AIDS are immunodeficient, receive multiple antibiotic treatments, occasionally anti-cancer chemotherapy and are often hospitalised; thus they are susceptible to develop a Clostridium difficile infection. The aim of this study was to evaluate the role of C. difficile in diarrhoea in this patient population. Therefore, C. difficile and toxin A which plays a major role in pathogenicity were examined in faecal samples of HIV infected patients. Between January 1991 and June 1992, 102 stool samples from 67 patients were studied. Ninety p. cent of these patients were hospitalised (length > 3 days), 80% had a diagnosis of AIDS stage IV, and 66% had diarrhoea. Nineteen point four p. cent of the patients were carriers of C. difficile. Different associations were found: 1) presence of non toxigenic strains and absence of toxin A in stool samples (6 patients), 2) presence of toxigenic strains and absence of toxin A in stool samples (6 patients), 3) presence of toxigenic strains and toxin A in stool samples (2 patients). None of the patients developed a colitis or pseudomembranous colitis. The carrier rate was identical to those found in other hospitalised populations without AIDS. The prevalence of C. difficile diarrhoea or colitis is low. In this study, AIDS patients do not seem to constitute a risk group for C. difficile intestinal pathology. However, carriers of C. difficile were subjected to strict hygiene rules to prevent nosocomial spread.

Polymerase chain reaction-based detection of hepatitis D virus genome in patients infected with human immunodeficiency virus.

The polymerase chain reaction (PCR) was used to detect hepatitis D (HD) viremia in patients infected with the human immunodeficiency virus (HIV). Nineteen (9%) of 206 such patients, unselected for liver disease or HBV infection, were found prospectively to be infected by HDV. Thirty-one anti-HIV-positive patients were studied by means of PCR, and the results were analyzed according to HDV and hepatitis B virus (HBV) serological status. HDV-PCR was positive in 5 patients. Two had detectable serum HDV antigen. Four patients had anti-HD IgM and IgG antibodies. All these patients were HBs antigen-positive, and 3 were HBV-DNA-positive. All the other patients were HDV-PCR-negative. Statistical analysis suggested more extensive liver damage and immunological impairment in HDV-PCR-positive patients. In this unselected HIV-infected population, HDV-RNA detection by PCR was restricted to HDV infected patients in whom 5/19 were positive. This test permitted direct diagnosis of HDV viremia and will be useful for monitoring HDV infection.

Polymerase chain reaction-based detection of hepatitis D virus RNA in patients infected with human immunodeficiency virus.

We used the polymerase chain reaction (PCR) to detect hepatitis D (HD) viremia in patients infected with the human immunodeficiency virus (HIV). Nineteen (9%) of 206 such patients were prospectively found to be infected by HDV. Thirty-one anti-HIV-positive patients were studied by means of PCR and the results were analysed according to HDV and hepatitis B virus (HBV) serological status. HDV-PCR was positive in five patients. Two had detectable serum HDV antigen. Four patients had anti-HD IgM and IgG antibodies. All these patients were HBs antigen-positive, and three were HBV-DNA positive. All the other patients were HDV-PCR-negative. Statistical analysis suggested more extensive liver damage and immunological impairement in HDV-PCR positive patients. In this unselected HIV-infected population, HDV-RNA detection by PCR was only evidenced in HDV infected patients in whom 5/19 were positive. This test allowed direct diagnosis of HDV viremia and will be useful for the monitoring of HDV infection.

Emergence during unsuccessful chemotherapy of multiple drug resistance in a strain of Mycobacterium tuberculosis.

Serial isolates of Mycobacterium tuberculosis were cultured from a patient who failed to respond to standard antituberculous chemotherapy. Isolates were cultured in March 1989, July 1989, December 1989 and May 1990. Each successive isolate was found to be resistant to a wider range of antituberculous drugs than its predecessors. The initial isolate was resistant to isoniazid and rifampin, the second isolate was also resistant to ethambutol, the third was also resistant to pyrazinamide, ansamycin (= rifabutin) and ofloxacin and the last isolate was also resistant to ciprofloxacin and sparfloxacin. All four isolates' bacteriophage typing profiles and DNA restriction fragment patterns determined by Southern blot hybridization using the IS6110/IS986 probes and the new probe pTBN12 were concordant. It was concluded that this patient was persistently infected with a single strain of Mycobacterium tuberculosis which developed resistance to a number of families of drugs but did not show any significant change in typing patterns. The problem of acquired multiple drug resistance, particularly to fluoroquinolones and rifamycins, represents a new challenge in tuberculosis therapy.

Sonography and computed tomography of macroscopic tuberculosis of the liver.

Four patients with macronodular tuberculosis of the liver were examined with ultrasonography. The findings included 1 case with multiple hypoechoic areas and 3 cases with a solitary lesion, one hypoechoic mass without calcifications, and two partially calcified masses. Some ultrasound features are suggestive: a mass with irregular calcifications, ascites, spleen enlargement with defects, enlarged nodes, and complete resolution of the lesions in a few months with effective antituberculous therapy. The first case was also examinated with computed tomography.