Long-term virological outcomes, failure and acquired resistance in a large cohort of Ugandan children.

OBJECTIVES: To evaluate long-term virological failure (VF) and drug resistance among HIV-infected Ugandan children on first-line ART. METHODS: In a multicentre prospective cohort study, viral load (VL) and drug resistance mutations (DRMs) were investigated at baseline and 6 monthly intervals in children (age ≤ 12 years). VF (two consecutive VLs >1000 copies/mL or death after 6 months of ART) was defined as early VF (0-24 months of ART) or late VF (25-48 months of ART). An active regimen was defined as partially active if the genotypic susceptibility score (GSS) was <3. RESULTS: Between 2010 and 2011, 316 children were enrolled. Viral suppression was achieved in 75.8%, 71.5%, 72.6% and 69.2% at 12, 24, 36 and 48 months. VF occurred in 111/286 (38.8%), of which 67.6% was early and 32.4% late VF. Early VF was associated with a partially active regimen at baseline (OR 6.0, 95% CI 1.9-18.5), poor adherence (OR 3.1, 95% CI 1.3-7.4) and immunodeficiency (OR 3.3, 95% CI 1.1-10.2). Late VF was associated with age >3 years (OR 2.5, 95% CI 1.0-6.6) and WHO stage 3/4 (OR 4.2, 95% CI 1.4-13.4). Acquired DRMs were detected in 27.0% before 24 months, versus 14.4% after 24 months (P < 0.001). A total of 92.2% of the children with early VF, versus 56.2% with late VF, had a partially active regimen (P < 0.001). CONCLUSIONS: VF rates were high, occurred predominantly in the first 24 months and appeared to increase again in year four. Risk factors and patterns of early VF/DRMs were different from those of late VF/DRMs. Virological control may improve by close monitoring and prompt switching to second-line therapy in the first 24 months. Late VF may be prevented by early start of ART.

Field study of dried blood spot specimens for HIV-1 drug resistance genotyping.

Dried blood spots (DBS) are an alternative specimen type for HIV drug resistance genotyping in resource-limited settings. Data relating to the impact of DBS storage and shipment conditions on genotyping efficiency under field conditions are limited. We compared the genotyping efficiencies and resistance profiles of DBS stored and shipped at different temperatures to those of plasma specimens collected in parallel from patients receiving antiretroviral therapy in Uganda. Plasma and four DBS cards from anti-coagulated venous blood and a fifth card from finger-prick blood were prepared from 103 HIV patients with a median viral load (VL) of 57,062 copies/ml (range, 1,081 to 2,964,191). DBS were stored at ambient temperature for 2 or 4 weeks or frozen at -80 °C and shipped from Uganda to the United States at ambient temperature or frozen on dry ice for genotyping using a broadly sensitive in-house method. Plasma (97.1%) and DBS (98.1%) stored and shipped frozen had similar genotyping efficiencies. DBS stored frozen (97.1%) or at ambient temperature for 2 weeks (93.2%) and shipped at ambient temperature also had similar genotyping efficiencies. Genotyping efficiency was reduced for DBS stored at ambient temperature for 4 weeks (89.3%, P = 0.03) or prepared from finger-prick blood and stored at ambient temperature for 2 weeks (77.7%, P < 0.001) compared to DBS prepared from venous blood and handled similarly. Resistance profiles were similar between plasma and DBS specimens. This report delineates the optimal DBS collection, storage, and shipping conditions and opens a new avenue for cost-saving ambient-temperature DBS specimen shipments for HIV drug resistance (HIVDR) surveillances in resource-limited settings.

Update on World Health Organization HIV drug resistance prevention and assessment strategy: 2004-2011.

The HIV drug resistance (HIVDR) prevention and assessment strategy, developed by the World Health Organization (WHO) in partnership with HIVResNet, includes monitoring of HIVDR early warning indicators, surveys to assess acquired and transmitted HIVDR, and development of an accredited HIVDR genotyping laboratory network to support survey implementation in resource-limited settings. As of June 2011, 52 countries had implemented at least 1 element of the strategy, and 27 laboratories had been accredited. As access to antiretrovirals expands under the WHO/Joint United Nations Programme on HIV/AIDS Treatment 2.0 initiative, it is essential to strengthen HIVDR surveillance efforts in the face of increasing concern about HIVDR emergence and transmission.

Surveillance of transmitted HIV-1 drug resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005-2009.

Surveillance of human immunodeficiency virus type 1 transmitted drug resistance (TDR) was conducted among pregnant women in South Africa over a 5-year period after the initiation of a large national antiretroviral treatment program. Analysis of TDR data from 9 surveys conducted between 2005 and 2009 in 2 provinces of South Africa suggests that while TDR remains low (<5%) in Gauteng Province, it may be increasing in KwaZulu-Natal, with the most recent survey showing moderate (5%-15%) levels of resistance to the nonnucleoside reverse transcriptase inhibitor drug class.

Surveillance of HIV drug resistance in children receiving antiretroviral therapy: a pilot study of the World Health Organization's generic protocol in Maputo, Mozambique.

Between 2007 and 2008, the Mozambique Ministry of Health conducted an assessment of human immunodeficiency virus drug resistance (HIVDR) using World Health Organization (WHO) methods in a cohort of children initiating antiretroviral therapy (ART) at the main pediatric ART referral center in Mozambique. It was shown that prior to ART initiation 5.4% of children had HIVDR that was associated with nevirapine perinatal exposure (P < .001). Twelve months after ART initiation, 77% had viral load suppression (<1000 copies/mL), exceeding the WHO target of ≥ 70%; 10.3% had HIVDR at 12 months. Baseline HIVDR (P = .04), maternal prevention of mother-to-child transmission (P = .02), and estimated days of missed medication (P = .03) predicted HIVDR at 12 months. As efforts to eliminate pediatric AIDS are intensified, implementation of ritonavir-boosted protease inhibitor regimens in children with prevention of mother-to-child transmission exposure may reduce risk of virological failure in our setting.

Hospital-acquired candidemia in HIV-infected patients. Incidence, risk factors and predictors of outcome.

A retrospective case-control study was performed to analyze hospital-acquired candidemia in HIV-positive patients. To understand the impact of Highly Active Antiretroviral Therapy (HAART) on the incidence of nosocomial candidemia, two time periods were compared: A (1992-1996) and B (1997-2001). 32 out of 38 (84%) cases of candidemia were hospital-related. A significant reduction in the incidence of all cases of hospital-acquired candidemia has been observed in the post-HAART in respect to pre-HAART period (0.09 episodes vs. 1.1 per 100/py). Multivariate analysis showed that the presence of central venous catheter was the only variable independently associated with the development of nosocomial candidemia. The overall mortality rate was 59%. Univariate analysis indicated three prognostic indicators: presence of concomitant opportunistic infections, isolation of non-albicans Candida species; neutropenia. Multivariate analysis of prognostic indicators showed that isolation of non-albicans Candida species is the only independent variable. Despite the use of HAART, this disease still represents a severe complication of advanced stage of AIDS.

Impact of highly active antiretroviral therapy (HAART) on the incidence of bacterial infections in HIV-infected subjects.

The aim of this study was to evaluate the effect of highly active antiretroviral therapy (HAART) on the incidence of bacterial infections in HIV-infected patients. Two time periods were compared: (A) January 1992-December 1995 (before HAART) and (B) January 1997-December 2000 (after HAART). During the study periods, we observed 931 patients with bacterial infections, i.e. 322 with bacteremia, 369 with bacterial pneumonia and 240 with urinary tract infections, out of 4,242 HIV-infected subjects admitted to the Department of Infectious Diseases of a large university hospital. By comparing the overall incidence of bacterial infections during periods A and B, a statistically significant difference, from 32% to 18% (p<0.01), was observed. Analysis of risk factors of community- and hospital-acquired bacterial infections did not significantly differ in the two study periods. This study establishes that a significant reduction in bacterial infection incidence occurred in HIV-infected subjects when HAART became the standard therapy for HIV infection.

Case report: Retinopathy after malaria prophylaxis with chloroquine.

Chloroquine retinopathy (CR) is a major complication of long-term malaria prophylaxis (LTMP) causing permanent visual dysfunction and occasionally blindness. After an extensive review of the published accounts of CR, we concluded that the risk of retinopathy in subjects receiving LTMP is limited to a cumulative dose that does not exceed 140 g. We present a case of CR that occurred after 8 years of malaria prophylaxis with chloroquine at a cumulative dose of 125 g. Because a threshold dose of chloroquine for retinal toxicity has not been established, careful, ongoing screening is required, especially as the cumulative dose increases.

Changes in incidence and risk factors of Mycobacterium avium complex infections in patients with AIDS in the era of new antiretroviral therapies.

The aim of the study presented here was to determine the incidence, risk factors and prognostic indicators of Mycobacterium avium complex (MAC) infection in HIV-infected subjects prior to and after the introduction of highly active antiretroviral therapy (HAART). In the HAART era, the incidence of MAC infection decreased significantly from 3.7 to 0.9 per 100 person-years. Using logistic regression analysis, a high acute physiology and chronic health evaluation (APACHE) III score, a low number of CD4+ cells/ mm3 and a high level of HIV viremia were found to be independent predictors of the risk to develop MAC disease; however, a high APACHE III score was the only prognostic indicator associated with an unfavourable outcome of a disseminated MAC infection. These results indicate that MAC infections, although considerably less frequent in the HAART era, are still responsible for cases of severe disease.

Nosocomial bacterial pneumonia in human immunodeficiency virus infected subjects: incidence, risk factors and outcome.

The presented study examined the incidence, risk factors and outcome of nosocomial bacterial pneumonia (NBP) in human immunodeficiency virus (HIV)-infected subjects. Forty-two cases of NBP were ascertained by a 5-yr prospective surveillance and were matched to 84 controls. NBP incidence was 10.8 per 10,000 hospital patient-days. In particular, the incidence of NBP was 13.9 per 10,000 patient-days in the period 1994-1996 and 5.6 per 10,000 patient-days in the period 1997-1998 (p=0.01). By using regression analysis, predictors for developing NBP were an increasing value of Acute Physiology and Chronic Health Evaluation (APACHE) III score (p<0.01) and the presence of acquired immune deficiency syndrome (AIDS)-related central nervous system (CNS) diseases (p=0.01). The additional hospital stay attributable to NBP was 15 days. The attributable mortality rate was estimated to be 29%. Nosocomial bacterial pneumonia is more common in patients with advanced human immunodeficiency virus infection, high Acute Physiology and Chronic Health Evaluation III score and central nervous system diseases. Although the incidence of nosocomial bacterial pneumonia, as well of other opportunistic infections, decreased considerably in the era of highly active antiretroviral therapy, it still represents an important cause of mortality.

Effect of highly active antiretroviral therapy on the incidence of bacterial pneumonia in HIV-infected subjects.

The aim of the study was to assess the incidence of hospital and community acquired bacterial pneumonia in HIV-infected subjects prior to and after the introduction of highly active antiretroviral therapy (HAART). We studied 266 patients with bacterial pneumonia over two separate periods, 154 in the first period and 112 in the second period. A statistically significant difference in the incidence of bacterial pneumonia in the two study periods was observed ranging from 13.1 to 8.5 episodes per 100 persons. The incidence of community-acquired bacterial pneumonia decreased from 10.7 to 7.7 (P=0.01), while that of nosocomial episodes decreased from 2.4 to 0.8 episodes (P=0.003). Low levels of peripheral CD(4+) cells (<100/mm(3)) and intravenous drug abuse (IVDA) were significantly associated with the development of community-acquired bacterial pneumonia, while an increasing value of APACHE III score and prolonged hospitalisation increased the risk of nosocomial bacterial pneumonia in both study periods.

Morbidity associated with central venous catheter-use in a cohort of 212 hospitalized subjects with HIV infection.

Technical complications and nosocomial bloodstream infections associated with short-term central venous catheterization remain a heavy burden in terms of morbidity, mortality and cost in HIV-positive subjects. Between 1994 and 1997, 327 central venous catheters (CVCs) inserted in 212 patients for a total of 5005 catheter days were investigated. Forty-two technical complications (13%) occurred in 40 patients. Logistic regression analysis revealed that a high APACHE III score was associated with development of CVC-related complications (P = 0.01). One hundred and eight of 327 CVCs (33%) were suspected as being infected. However only 61 episodes (61/327, 19%) were finally diagnosed as CVC-related sepsis. Three variables affecting the rate of CVC-related sepsis were identified: 1) administration of TPN (P = 0.01); 2) low number of circulating CD4+ cells (P = 0.04); 3) high APACHE III score (P = 0. 04). Doctors responsible for AIDS patients should carefully consider the relative risks and benefits of CVC insertion in an individual patient.

[Central venous catheter-related sepsis: one year experience in a large university hospital] / Sepsi in pazienti con cateteri venosi centrali: un anno di esperienza in un policlinico universitario.

Five hundred two central venous catheters (CVC) inserted in 366 patients were evaluated prospectively over a one-year period to determine the frequency and risk factors associated with CVC-related sepsis. A CVC-related infection was suspected in 190 cases (190/502, 38%). A catheter-related sepsis was established in 50 patients (10%). The infection rate was 0.8 cases of sepsis per 100 catheterdays. Staphylococcus epidermidis, Staphylococcus aureus, and Candida spp. were the most frequently isolated etiological agents of sepsis. On univariate analysis, six variables affecting the rate of catheter-related sepsis were identified: neutropenia > 8 days (p < 0.01); AIDS (p < 0.001); haematological malignancies (p < 0.001); total parenteral nutrition (p = 0.001); duration of site use (p = 0.04); high APACHE II score (p = 0.04). The logistic regression analysis revealed that AIDS and haematological malignancies were independent risk factors of catheter-related sepsis. In conclusion, although the incidence of established catheter infection is much lower than the incidence of suspected infection, in most cases it is wise to change the catheter with the guidewire technique and wait for culture of the tip, rather than to remove the catheter immediately.