Dan Duiculescu

Lipid Levels and Changes in Body Fat Distribution in Treatment-Naive, HIV-1–Infected Adults Treated With Rilpivirine or Efavirenz for 96 Weeks in the ECHO and THRIVE Trials

BACKGROUND Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials. METHODS We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1). RESULTS Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t]RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV- than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it. CONCLUSIONS Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid parameters and fewer dyslipidemia AEs than EFV-based treatment. Body fat distribution changes were similar between treatments. The N[t]RTI regimen affected lipid and body fat distribution changes.

Transmitted HIV drug resistance in treatment-naive Romanian patients.

Transmitted HIV drug resistance (TDR) remains an important concern for individuals unexposed to antiretroviral treatment. Data on the prevalence of TDR, available mainly for HIV‐1 subtype B, are now also emerging for other subtypes. In Romania, a steady predominance of subtype F was reported among both long‐term survivor children and newly infected adults. The pol gene of 61 drug‐naïve patients infected with HIV, diagnosed between 1997 and 2011 was sequenced in order to analyze the prevalence of primary resistance mutations and to correlate these with the infecting genotype. Only 5/61 specimens were classified as infected recently using the BED‐Capture Enzyme Immunoassay. Subtype F1 was prevalent (80.3%), however, other HIV‐1 clades are increasingly identified, especially in the group of subjects infected recently. An HIV transmission cluster, associated to injecting drug use was identified by phylogenetic analysis. The overall prevalence of TDR was 14.75%, mainly associated with NRTI resistance (13.11%), TAMs and M184V being the most common mutations. A declining trend of TDR was recorded from 26.08% in 1997–2004 to 7.89% in 2005–2011. No primary resistance was identified among recent seroconvertors. All HIV‐1 strains had minor mutations in the protease and RT genes, often detected at polymorphic positions. The declining rates of TDR might be related to the high efficacy of HAART and to the increasing number of treated patients with virological success who have a low risk of transmission. The recent increase of HIV‐1 infections which involve other subtypes impose a continuous surveillance of the genetic composition of the epidemic. J. Med. Virol. 85:1139–1147, 2013.

High prevalence of asymptomatic HBV chronic carriage in HIV infected long term survivors

Hepatitis B virus (HBV) infection is common in individuals infected with human immunodeficiency virus, and coinfection is associated with higher rates of HBV replication and more rapid liver disease progression than HBV monoinfection. This study evaluates the prevalence and virological profiles of hepatitis B infection in a cohort of long term survivors, with multiple antiretroviral treatments. 164 HIV-infected subjects (median age: 24 years) on combined antiretroviral therapy (cART) (median duration: 13 years), were evaluated for serologic markers of HBV infection (HBsAg, total anti-HBc and anti-HBsAg antibodies). Markers of HBV infectivity (HBeAg and HBV DNA) were evaluated in all HBsAg carriers; HBV genotype and lamivudine resistance mutations were analyzed in the cases with HBV DNA >103 IU/mL. 65.9% of the patients (108/164) had markers of past or present HBV infection (antiHBc positives), out of which 51.8% (56/108) were chronic HBV carriers and 30.5% had resolved HBV infection. All subjects were equally exposed to HBV infection, irrespective of their current immune status. Out of 21 patients with isolated anti-HBc antibodies, only 4 had detectable HBV DNA, presumably having occult hepatitis B. HBV chronic carriage rate was not influenced by the immune status. Overall, only 17.8% of the chronic carriers had active HBV replication; severely immune-depressed patients tend to maintain active viral replication more frequently than those with moderate or absent immunosuppression. The majority of the coinfected individuals (68.3%) showed no sign of liver fibrosis (APRI score 1.5); HBV DNA was directly correlated with APRI score. HBV genotype A was present in all but one of the tested patients. 98.8% of the coinfected subjects have been treated with a cART regimen that includes a drug dually active against HIV and HBV (in 98% of the cases lamivudine (3TC), for a mean time of 6.9 years and in 29.7% of the cases the current dually active drug was tenofovir). 3TC-resistance mutations were present in only 4 coinfected subjects. We found a strikingly low percentage of long term HIV/HBV coinfected patients from our group with active liver disease. A high prevalence of asymptomatic HBV chronic carriage was associated with a good immune status, suggesting that dually active antiretrovirals have an important role in delaying progression of liver disease in HIV/HBV coinfected patients.

Cerebral toxoplasmosis in children and adolescents from “Dr. Victor Babeş” Hospital pediatric HIV-cohort

Cerebral toxoplasmosis (Toxo) is rarely described in children. The Romanian pediatric cohort consists of children that have been infected parenterally in the late ’80s. We aimed to describe the prevalence, clinical findings and outcome of Toxo in children and adolescents from the Romanian Pediatric Cohort, that have been diagnosed in the “Dr. Victor Babes” Hospital, one of the main reference centers for HIV from Romania Cerebral toxoplasmosis was diagnosed based on CDC case definition (presumptive and definitive diagnosis). We reviewed retrospectively the charts of all 29 children diagnosed with Toxo starting 1996, recording the demographic, HIV markers, antiretroviral treatment, clinical and neuroimaging data, treatment and outcome of Toxo. The prevalence of Toxo was 4.8% from 604 patients followed in the Hospital. Out of 29 patients diagnosed with Toxo, 19 were girls and 28 had parenterally and 1 had vertically acquired HIV. The mean age at HIV diagnosis was 11.5±6.5 years, and 15.6±5.3 years at Toxo diagnosis. In 10 patients HIV was diagnosed concomitantly with Toxo. At onset 89.7% patients had focal neurological signs and 62.1% had headache. Median CD4 count was 60 (95% CI for median 27-95) lf/cmm. 28 patients had positive T. gondii IgG antibodies in plasma and/or cerebrospinal fluid. Only 6 patients had treatment with cotrimoxazole, most of them being treated with pyrimethamine/sulphadoxine combination and alternatively with atovaquone. 69% of patients had any adverse reactions to Toxo treatment. Most adverse reactions were cutaneous in 10 patients (5 severe) and anemia in 7 patients. Nine patients had antiretroviral therapy (ART) before Toxo diagnosis, out of them 1 had mono, 1 dual therapy, 6 were failing cART and one patient had immune reconstitution syndrome. Ten patients (34.5%) died. The median survival time was 117 months. In univariate analysis survival was correlated with shorter time from onset to admission (p=0.04) while on multivariate analysis diagnosis in the post-cART period was the only factor associated with longer survival (p=0.03). 14 of 19 patients recovered with sequels, most of them motor deficits. Cerebral toxoplasmosis in this particular pediatric cohort shared common features with that reported in adults pertaining to prevalence in pre-cART period and pathogenic mechanism. Survival was associated with a more rapid diagnosis of cerebral toxoplasmosis and with access to cART.

Cervical HPV infection in Romanian women infected with HIV during early childhood.

Human papillomavirus (HPV) is the most common cause of cervical cancer worldwide, and Romania has the highest rate of cervical cancer in Europe. Sixty-five young Romanian women infected with HIV during early childhood and 25 control subjects were evaluated for the presence of cervical HPV infection and for cytologic abnormalities. HPV infection was evaluated longitudinally in 42 HIV-infected individuals. Overall 28/65 (43.1%) of HIV-infected and 8/25 (32.0%) of uninfected subjects were infected with HPV, and 21/65 (32.3%) and 6/25 (24%) had high-risk subtypes, respectively. In HIV-infected women, those maintaining or acquiring a new subtype in follow-up were more likely to have a lower nadir (p = 0.04) and current (p = 0.01) CD4 cell counts. The incidence rate for HPV acquisition events was 0.69 per subject per year, and 0.52 for high-risk subtypes. In the HIV-infected group, 9/13 (69.2%) individuals with abnormal cytology progressed at follow-up. Although HPV prevalence was similar to controls, the rate of Pap smear abnormalities was much higher, possibly due to the decreased ability to mount new immune responses. Given the high rate of incident detection of vaccine preventable strains and cytologic progression in this cohort, HPV vaccination may be beneficial at any age in co-infected women.

Serodiagnosis of environmental mycobacterial infections.

To demonstrate the usefulness of enzyme-linked immunosorbent assay for serodiagnosis of mycobacterioses due to environmental mycobacteria we utilized a panel of glycolipid antigens selective for Mycobacterium avium-intracellulare, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium scrofulaceum and Mycobacterium gordonae. The levels of circulating antibodies were determined against the environmental mycobacteria, and Mycobacterium tuberculosis in human immunodeficiency virus-negative and -positive patient sera. The method used immunomagnetic separation of the antigens, with covalent immobilization of antibodies to superparamagnetic amine and carboxyl terminated particles in solutions of the specific antigens. Enzyme-linked immunosorbent assay was performed on 195 patient sera: 34 with infections due to environmental mycobacteria, 114 with tuberculosis, 47 with other respiratory diseases. There were 46 human immunodeficiency virus-1 infected individuals. Among the 34 infections due to environmental mycobacteria, 9 patients were singularly infected with an environmental mycobacterium, and 25 co-infected with both M. tuberculosis and an environmental mycobacterium. Sensitivity, specificity and false positivity ranges were determined for each of the volunteer groups: tuberculosis positive, human immunodeficiency virus negative; tuberculosis positive, human immunodeficiency virus positive; those with infections due to individual environmental mycobacteria (such as M. scrofulaceum and M. kansasii); and those with other respiratory diseases. We demonstrate that such multiple assays, can be useful for the early diagnosis of diverse environmental mycobacterial infections to allow the start of treatment earlier than henceforth.

Phagocytic function of monocytes in children with human immunodeficiency virus type 1 infection.

ABSTRACT We investigated the phagocytic function of monocytes in 7- to 10-year-old children horizontally infected with human immunodeficiency virus type 1 (HIV-1) in comparison to that in healthy sex- and age-matched controls. CR3-mediated phagocytosis was increased in patients with HIV-associated pulmonary tuberculosis, independently of CD4 counts and p24 antigenemia.

Extrapulmonary tuberculosis in HIV infected patients from the cohort of “Dr Victor Babeş” Hospital, Bucharest, Romania

The infection with Mycobacterium tuberculosis remains the most frequent opportunistic infection in HIV seropositive patients. In Romania the incidence of tuberculosis (TB) in general population is the highest in Europe with 70.9 per 10,000 inhabitants. We investigated the incidence of extrapulmonary tuberculosis in “Dr Victor Babes” Hospital cohort and its epidemiological, clinical and outcome particularities. We performed an observational retrospective study during 2003-2013 among the HIV infected patients from our cohort. We selected the patients with extrapulmonary tuberculosis. The data was obtained from the medical charts and outpatient records. From 280 cases of confirmed infection we found 55 cases of extrapulmonary tuberculosis. The HIV transmission route was parenteral in 72.55% (95%CI 58.75 to 87.40) of cases. The median age at TB diagnosis was 24 years (95%, CI 20.16 to 25.03) with male/female ratio of 1,21. At the time of TB diagnosis the median CD4 count was 87 cells/cmm (95% CI 72.87 to 131.31). The percent of patients with concomitant pulmonary and extrapulmonary localization was 57.7% (95% CI 40.79 to 72.78). The number of patients with recurrent TB was 17 and 5 had more than one extrapulmonary TB in the studied period. The most frequent extrapulmonary involvement was ganglionar 35/51 (69.7% 95% CI 54.91 to 79.74). The commonest manifestations were fever (57.5% 95% CI 40.79 to 72.78), weight loss (30% 95% CI 17.25 to 47.46) and adenopathy (24.2% 95% CI 12.60 to 41.25) and the median time from the onset to diagnosis was 4 weeks (95% CI 2.611 to 5.209). In 54.5% (95% CI 40.79 to 72.78) of cases the smear was positive, cultures were positive in 69.7% (95% CI 55.61 to 85.10) and in 30% (95% CI 17.25 to 47.46) of cases the diagnosis was made on histopathologic examination. In 45.5% (95% CI 32.50 to 64.78) we obtained an antibiogram that confirmed MDR TB in 11.5% (95% CI 2.37 to 24.34). All patients received treatment and 7.84% (95% CI 6.17 to 31.40) abandoned treatment and 11.76% (95% CI 2.37 to 23.4) died. Although the extrapulmonary involvement is not very frequent, the diagnosis can be challenging and can take a lot of time especially when it is difficult to obtain a specimen. In a febrile immunodepressed patient extrapulmonary TB should be always considered.