Maria Stella Mura

Severe liver disease associated with prolonged exposure to antiretroviral drugs

Background: Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals. Methods: Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status. Results: CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population. Conclusions: CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent.

Alendronate Reduces Bone Resorption in HIV-Associated Osteopenia/Osteoporosis

Abstract Purpose: To evaluate the effects of alendronate, vitamin D, and calcium supplementation on bone metabolism and bone mineral density (BMD) in both HIV-infected men and women treated with highly active antiretroviral therapy (HAART). Method: We performed a 52-week prospective, multicenter, randomized, open-label clinical trial. Eligible participants were on stable HAART and had BMD values at the femoral neck or lumbar spine that corresponded to a t score less than -1. Patients were randomized to receive alendronate 70 mg weekly or no alendronate; calcium 1000 mg daily and vitamin D 500 IU daily were provided to all study recipients. Primary endpoint of the study was the change in bone metabolism evaluated by N-telopeptide of type 1 collagen and bone-specific alkaline phosphatase; the secondary endpoint was BMD variation. Results: 18 patients were randomized to the alendronate and 23 to the no-alendronate group (controls). The alendronate-treatment group compared to controls had a significant decrease in serum N-telopeptides, 1914 ± 1433.4 vs. 3967 ± 1650.5 pM/L (p = .005) after 1 year. Lumbar spine BMD increased by 4% in the alendronate group (p = .004) vs. 3.7% (p = .062) in controls, compared to baseline values. Femoral neck BMD decreased by 0.5% in the alendronate group (p = .05) and by 3.5% in the control group (p = .04). No between-groups differences for BMD were found (Δ lumbar-BMD 0.0351 ± 0.0406 in cases and 0.0356 ± 0.073 in controls [p = .977], Δ femoral-BMD –0.085 ± 0.160 in cases and –0.100 ± 0.165 in controls [p = .795]). Conclusion: Alendronate plus vitamin D and calcium was effective in reducing bone resorption. Alendronate improved lumbar BMD and minimized femoral BMD decrease after 52 weeks compared to treatment with vitamin D and calcium alone in patients on HAART with osteopenia/osteoporosis.

Treatment-related factors and highly active antiretroviral therapy adherence.

Summary: Adherence to highly active antiretroviral therapy (HAART) plays a critical role in the effectiveness of HIV treatment. Nevertheless, the complexity of regimens and frequent side effects make HAART extraordinarily difficult to take, and many HIV‐infected persons fail to adhere. The current study offers an overview of the relationship between adherence and antiretroviral treatment‐related variables. As for other chronic diseases, medication regimen complexity also has an impact on adherence in the management of HIV infection. In particular, the authors discuss the effect of pill burden, dosing frequency, dietary instructions, number and type of different medications prescribed, short‐ and long‐term side effects, convenience, and ability to incorporate the treatment regimen into a daily routine. Medication side effects are common in HAART‐treated persons and are associated with concurrent and future nonadherence. Simplification of regimens, adjustment of the drug schedule to the patients specific lifestyle, and anticipation and self‐management of side effects are treatment‐based strategies to optimize HAART adherence and ensure the most effective, convenient, safe, and well‐tolerated antiretroviral treatment.

Thyroid function in human immunodeficiency virus patients treated with highly active antiretroviral therapy (HAART): a longitudinal study

Objective  Given that few and controversial data have been reported on thyroid function in human immunodeficiency virus (HIV) patients on highly active antiretroviral therapy (HAART), we further investigated whether HAART affects thyroid hormones.

Incidence of Neutropenia and Infections During Combination Treatment of Chronic Hepatitis C with Pegylated Interferon Alfa-2a or Alfa-2b Plus Ribavirin

Background:Combination therapy with pegylated interferon (peginterferon) plus ribavirin is associated with several side effects, including neutropenia and infection.Aims:To evaluate the incidence of neutropenia and infection between all consecutive patients with hepatitis C who were treated in two centers with peginterferon-alfa-2a and peginterferon-alfa-2b, in combination with ribavirin and actively monitored for occurrence of any infection. Methods:A total of 319 consecutive patients with chronic hepatitis C received once-weekly peginterferon alfa-2b at a weight-adjusted dose (n = 162) or peginterferon alfa-2a at a flat dose (n = 157), plus ribavirin.Results:Neutropenia was observed in 53 patients overall (17%). There were 73 infections in 73 subjects (23% of the treated population); 4/73 required hospitalization. Infections included respiratory infections (n = 23), cellulitis (n = 17), dental abscesses (n = 13), gastroenteric infections (n = 2), and other types of infections (n = 18). The incidence of all infections was significantly associated with age, especially over 60 years (p < 0.01) but not with neutropenia or type of pegylated interferon.Conclusions:During the treatment with pegylated interferons and ribavirin, we did not find a correlation between neutropenia and infections. This result provides a support for the notion that current guidelines for pegylated interferons dose reduction in the treatment of chronic hepatitis C for hematologic toxicity could be overly strict.

Bacterial Community Acquired Pneumonia in HIV-Infected Inpatients in the Highly Active Antiretroviral Therapy Era

Introduction:Highly active antiretroviral therapy (HAART) has deeply modified HIV/AIDS related morbidity and mortality. However, bacterial community acquired pneumonia (BCAP) still represents one of the most frequent causes of morbidity in HIV-infected patients with an inpatient 10% mortality rate.Objectives:We retrospectively studied the characteristics of BCAP in consecutive HIV-infected inpatients hospitalized from 1999 to 2004 and evaluated the presence of risk factors and the influence of combination antiretroviral therapy receipt on BCAP outcomes.Results:We studied 84 BCAP episodes in 76 HIV-infected inpatients (63 males and 13 females) aged 27–80 years. Thirty-two (42.1%) patients were receiving combination antiretroviral treatment (CART) while 44 (57.9%) were not treated (NART). BCAP incidence progressively increased from 1999 to 2004. The overall percentage of injection drug users was > 84%, of smokers > 88% and alcohol abusers > 32% with no statistical difference between CART and NART. Streptococcus pneumoniae was the most frequently identified pathogen (60%). Time to clinical stability was significantly longer in NART in respect of CART (p = 0.011). In multivariate analysis, CDC stage C, CD4 cell count < 100 × 106 cells/l, and S. pneumoniae etiology were predictors for time to clinical stability > 7 days, while receipt of antiretroviral therapy was protective. The percentage of deaths did not differ between CART and NART; most patients had a CD4 count < 200 × 106 cells/l or severe concomitant diseases.Conclusions:The incidence of BCAP was high in HIV-infected inpatients observed in the present study mainly due to HIV infection itself, IVDU, alcohol abuse and smoking habit. A longer time to clinical stability was associated with advanced HIV infection and with S. pneumoniae etiology, while receipt of antiretroviral therapy was protective. Injection drug abuse treatment, alcohol abuse and smoking cessation programs, antiretroviral treatment adherence support and pneumococcal vaccination should be implemented to reduce the incidence and to improve the outcomes of BCAP in HIV-infected patients.

Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex: Evidence from the I.Co.N.A. study

Objectives of the study were to assess the differences between sexes in the likelihood of starting antiretroviral therapy (ART), in rates of sustained discontinuation from highly active antiretroviral therapy (HAART), and in clinical progression. In a multicenter cohort study (I.Co.N.A. Study), 2323 men and 1335 women previously naive to antiretrovirals were enrolled. As of September 2002, 807 women and 1480 men started ART. The median time to starting ART was 28 weeks for women and 17 weeks for men (P = 0.0003 by log-rank test). This difference was no longer significant after adjusting for either HIV RNA (P = 0.21) or CD4 count (P = 0.28) at enrollment. Women tend to start HAART less frequently than mono/dual ART after adjusting for potential confounders (odds ratio = 0.78, 95% confidence interval [CI]: 0.60-1.01; P = 0.06). Women who started HAART were 1.4 times more likely than men (95% CI: 1.00-1.99; P = 0.05) to interrupt at least 1 drug because of toxicity. Twenty-one percent of women and 19% of men interrupted HAART altogether for more than 3 months (P = 0.3). Clinical progression was observed in 53 women (22.6%) and 137 men (23.4%; P = 0.56). Risk of developing a clinical event was found to be no different between women and men (relative hazard = 0.84, 95% CI: 0.56-1.26; P = 0.40).

Minor Mutations in HIV Protease at Baseline and Appearance of Primary Mutation 90M in Patients for Whom Their First Protease-Inhibitor Antiretroviral Regimens Failed

The association between minor mutations in human immunodeficiency virus (HIV) protease at baseline and development of common primary mutation 90M at virological failure (conferring some resistance to all protease inhibitors [PIs]) was evaluated in 93 previously drug-naive patients experiencing failure of their first PI-based antiretroviral regimens. In logistic regression analysis, the probability of accumulating a new 90M mutation at virological failure was associated with the presence at baseline of minor mutation 36I (naturally occurring in approximately 25% of HIV clade B and in >80% of HIV non-clade-B viruses) (adjusted odds ratio, 13.5 [95% confidence interval, 1.89-95.6]; P=.009) and, possibly, of 10I/V. This suggests a potential role for the presence of 36I at baseline in predicting the appearance of 90M at virological failure.

Identification of HIV patients with active pulmonary tuberculosis using urine based polymerase chain reaction assay

BACKGROUND Despite the increased dissemination of tuberculosis among HIV infected patients, the diagnosis is difficult to establish. Traditional microbiological methods lack satisfactory sensitivity. We have developed a highly sensitive and specific nested polymerase chain reaction (PCR) capable of detecting Mycobacterium tuberculosis DNA in urine specimens and have used this test to examine urine specimens from HIV patients with active pulmonary tuberculosis. METHODS Urine specimens from 13 HIV infected patients with microbiologically proven active pulmonary tuberculosis, 10 AIDS patients with non-tuberculous mycobacterial infection (documented by blood culture), 53 AIDS patients with no evidence of mycobacterial disease, and 80 healthy subjects (25 with positive skin test to purified protein derivative) were tested forM tuberculosis using PCR, acid fast staining (AFS), and culture. RESULTS Of the urine specimens from patients with active tuberculosis, all tested positive by PCR, two by culture, and none by AFS. No reactivity was observed in urine specimens from patients with non-tuberculous mycobacterial infection. Of the 53 AIDS patients without mycobacterial infection, one had a positive urine PCR. Normal subjects were all negative. CONCLUSIONS Urine based nested PCR for M tuberculosis may be a useful test for identifying HIV patients with pulmonary tuberculosis.

Patients with pulmonary tuberculosis develop a strong humoral response against methylated heparin-binding hemagglutinin.

ABSTRACT Reactivities of human sera against selected recombinant Mycobacterium tuberculosis antigens were assessed by enzyme-linked immunosorbent assay. The results obtained indicate that patients with tuberculosis (TB) do not develop a strong humoral response against PE_PGRS and PPE proteins or against the Ag85B and heparin-binding hemagglutinin (HBHA) recombinant antigens. Conversely, purified methylated HBHA was strongly recognized by sera obtained from TB patients compared to controls.