Determinants of Weight Evolution Among HIV-Positive Patients Initiating Antiretroviral Treatment in Low-Resource Settings.

BACKGROUND In resource-limited settings, clinical parameters, including body weight changes, are used to monitor clinical response. Therefore, we studied body weight changes in patients on antiretroviral treatment (ART) in different regions of the world. METHODS Data were extracted from the "International Epidemiologic Databases to Evaluate AIDS," a network of ART programmes that prospectively collects routine clinical data. Adults on ART from the Southern, East, West, and Central African and the Asia-Pacific regions were selected from the database if baseline data on body weight, gender, ART regimen, and CD4 count were available. Body weight change over the first 2 years and the probability of body weight loss in the second year were modeled using linear mixed models and logistic regression, respectively. RESULTS Data from 205,571 patients were analyzed. Mean adjusted body weight change in the first 12 months was higher in patients started on tenofovir and/or efavirenz; in patients from Central, West, and East Africa, in men, and in patients with a poorer clinical status. In the second year of ART, it was greater in patients initiated on tenofovir and/or nevirapine, and for patients not on stavudine, in women, in Southern Africa and in patients with a better clinical status at initiation. Stavudine in the initial regimen was associated with a lower mean adjusted body weight change and with weight loss in the second treatment year. CONCLUSIONS Different ART regimens have different effects on body weight change. Body weight loss after 1 year of treatment in patients on stavudine might be associated with lipoatrophy.

Modelling the impact of deferring HCV treatment on liver-related complications in HIV coinfected men who have sex with men

BACKGROUND AND AIMS Hepatitis C (HCV) is a leading cause of morbidity and mortality in people who live with HIV. In many countries, access to direct acting antiviral agents to treat HCV is restricted to individuals with advanced liver disease (METAVIR stage F3 or F4). Our goal was to estimate the long term impact of deferring HCV treatment for men who have sex with men (MSM) who are coinfected with HIV and often have multiple risk factors for liver disease progression. METHODS We developed an individual-based model of liver disease progression in HIV/HCV coinfected men who have sex with men. We estimated liver-related morbidity and mortality as well as the median time spent with replicating HCV infection when individuals were treated in liver fibrosis stages F0, F1, F2, F3 or F4 on the METAVIR scale. RESULTS The percentage of individuals who died of liver-related complications was 2% if treatment was initiated in F0 or F1. It increased to 3% if treatment was deferred until F2, 7% if it was deferred until F3 and 22% if deferred until F4. The median time individuals spent with replicating HCV increased from 5 years if treatment was initiated in F2 to almost 15 years if it was deferred until F4. CONCLUSIONS Deferring HCV therapy until advanced liver fibrosis is established could increase liver-related morbidity and mortality in HIV/HCV coinfected individuals, and substantially prolong the time individuals spend with replicating HCV infection.

Certolizumab treatment during late pregnancy in patients with rheumatic diseases: Low drug levels in cord blood but possible risk for maternal infections. A case series of 13 patients

OBJECTIVE Due to reduction of immune-suppressive drugs, patients with rheumatic diseases can experience an increase in disease activity during pregnancy. In such cases, TNF-inhibitors may be prescribed. However, monoclonal antibodies with the Fc moiety are actively transported across the placenta, resulting in therapeutic drug levels in the newborn. As certolizumab (CZP) lacks the Fc moiety, it may bear a lower risk for the child. METHOD We report a case series of thirteen patients (5 with rheumatoid arthritis and 8 with spondyloarthritis) treated with CZP during late pregnancy to control disease activity. RESULT CZP measured in cord blood of eleven infants ranged between undetectable levels and 1μg/mL whereas the median CZP level of maternal plasma was 32.97μg/mL. Three women developed an infection during the third trimester, of whom one had a severe infection and one had an infection that resulted in a pre-term delivery. During the postpartum period, 6 patients remained on CZP while breastfeeding. CZP levels in the breast milk of two breastfeeding patients were undetectable. CONCLUSION The lack of the active transplacental transfer of CZP gives the possibility to treat inflammatory arthritis during late gestation without potential harm to the newborn. However, in pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause prematurity. CZP treatment can be continued while breastfeeding.

Diagnosis of sexually transmitted infections in developing nations using syndromic management: Is it working?

Sexually transmitted infections (STIs) are a major public health problem, and controlling their spread is a priority. According to the World Health Organization (WHO), there are 340 million new cases of treatable STIs among 15–49 year olds that occur yearly around the world (1). Infection with STIs can lead to several complications such as pelvic inflammatory disorder (PID), cervical cancer, infertility, ectopic pregnancy, and even death (1). Additionally, STIs and associated complications are among the top disease types for which healthcare is sought in developing nations (1), and according to the UNAIDS report, there is a strong connection between STIs and the sexual spread of HIV infection (2). In fact, it is estimated that the presence of an untreated STI can increase the likelihood of contracting and spreading HIV by a factor up to 10 (2). In addition, developing countries are poorer in resources and lack inexpensive and precise diagnostic laboratory tests for STIs, thereby exacerbating the problem. Thus, the WHO recommends syndromic management of STIs for delivering care where lab testing is scarce or unattainable (1). This approach utilizes the use of an easy to use algorithm to help healthcare workers recognize symptoms/signs so as to provide treatment for the likely cause of the syndrome. Furthermore, according to the WHO, syndromic management offers instant and legitimate treatment compared to clinical diagnosis, and that it is also more cost-effective for some syndromes over the use of laboratory testing (1). In addition, even though it has been shown that the vaginal discharge syndrome has low specificity for gonorrhea and Chlamydia and can lead to over treatment (1), this is the recommended way to manage STIs in developing nations. Thus, the purpose of this paper is to specifically address the following questions: is syndromic management working to lower the STI burden in developing nations? How effective is it, and should it still be recommended? To answer these questions, a systematic literature review was conducted to evaluate the current effectiveness of syndromic management in developing nations. This review examined published articles over the past 5 years that compared syndromic management to laboratory testing and had published sensitivity, specificity, and positive predicative value data. Focusing mainly on vaginal discharge, urethral discharge, and genital ulcer algorithms, it was seen that though syndromic management is more effective in diagnosing and treating urethral and genial ulcer syndromes in men, there still remains an urgent need to revise the WHO recommendations for managing STIs in developing nations. Current studies have continued to show decreased specificity, sensitivity and positive predicative values for the vaginal discharge syndrome, and high rates of asymptomatic infections and healthcare workers neglecting to follow guidelines limit the usefulness of syndromic management. Furthermore, though advocate d as cost-effective by the WHO, there is a cost incurred from treating uninfected people. Instead of improving this system, it is recommended that better and less expensive point of care and the development of rapid test diagnosis kits be the focus and method of diagnosis and treatment in developing nations for STI management. ^

Case-control study of factors associated with virologic failure in HIV-infected children on HAART in Botswana, a developing African country

According to the United Nations Program on HIV/AIDS (UNAIDS, 2008), in 2007 about 67 per cent of all HIV-infected patients in the world were in Sub-Saharan Africa, with 35% of new infections and 38% of the AIDS deaths occurring in Southern Africa. Globally, the number of children younger than 15 years of age infected with HIV increased from 1.6 million in 2001 to 2.0 million in 2007 and almost 90% of these were in Sub-Saharan Africa. (UNAIDS, 2008).^ Both clinical and laboratory monitoring of children on Highly Active Anti-Retroviral Therapy (HAART) are important and necessary to optimize outcomes. Laboratory monitoring of HIV viral load and genotype resistance testing, which are important in patient follow-up to optimize treatment success, are both generally expensive and beyond the healthcare budgets of most developing countries. This is especially true for the impoverished Sub-Saharan African nations. It is therefore important to identify those factors that are associated with virologic failure in HIV-infected Sub-Saharan African children. This will inform practitioners in these countries so that they can predict which patients are more likely to develop virologic failure and therefore target the limited laboratory monitoring budgets towards these at-risk patients. The objective of this study was to examine those factors that are associated with virologic failure in HIV-infected children taking Highly Active Anti-retroviral Therapy in Botswana, a developing Sub-Saharan African country. We examined these factors in a Case-Control study using medical records of HIV-infected children and adolescents on HAART at the Botswana-Baylor Children's Clinical Center of Excellence (BBCCCOE) in Gaborone, Botswana. Univariate and Multivariate Regression Analyses were performed to identify predictors of virologic failure in these children.^ The study population comprised of 197 cases (those with virologic failure) and 544 controls (those with virologic success) with ages ranging from 3 months to 16 years at baseline. Poor adherence (pill count <95% on at least 3 consecutive occasions) was the strongest independent predictor of virologic failure (adjusted OR = 269.97, 95% CI = 104.13 to 699.92; P < 0.001). Other independent predictors of virologic failure identified were: First Line NNRTI with Nevirapine (OR = 2.99, 95% CI = 1.19 to7.54; P = 0.020), Baseline HIV-1 Viral Load >750,000/ml (OR = 257, 95% CI = 1.47 to 8.63; P = 0.005), Positive History of PMTCT (OR = 11.65, 95% CI = 3.04-44.57; P < 0.001), Multiple Care-givers (>=3) (OR = 2.56, 95% CI = 1.06 to 6.19; P = 0.036) and Residence in a Village (OR = 2.85, 95% CI = 1.36 to 5.97; P = 0.005).^ The results of this study may help to improve virologic outcomes and reduce the costs of caring for HIV-infected children in resource-limited settings. ^ Keywords: Virologic Failure, Highly Active Anti-Retroviral Therapy, Sub-Saharan Africa, Children, Adherence.^

Impact of real time polymerase chain reaction technology on the therapeutic approach to treatment of staphylococcal infections

Can the early identification of the species of staphylococcus responsible for infection by the use of Real Time PCR technology influence the approach to the treatment of these infections? ^ This study was a retrospective cohort study in which two groups of patients were compared. The first group, ‘Physician Aware’ consisted of patients in whom physicians were informed of specific staphylococcal species and antibiotic sensitivity (using RT-PCR) at the time of notification of the gram stain. The second group, ‘Physician Unaware’ consisted of patients in whom treating physicians received the same information 24–72 hours later as a result of blood culture and antibiotic sensitivity determination. ^ The approach to treatment was compared between ‘Physician Aware’ and ‘Physician Unaware’ groups for three different microbiological diagnoses—namely MRSA, MSSA and no-SA (or coagulase negative Staphylococcus). ^ For a diagnosis of MRSA, the mean time interval to the initiation of Vancomycin therapy was 1.08 hours in the ‘Physician Aware’ group as compared to 5.84 hours in the ‘Physician Unaware’ group (p=0.34). ^ For a diagnosis of MSSA, the mean time interval to the initiation of specific anti-MSSA therapy with Nafcillin was 5.18 hours in the ‘Physician Aware’ group as compared to 49.8 hours in the ‘Physician Unaware’ group (p=0.007). Also, for the same diagnosis, the mean duration of empiric therapy in the ‘Physician Aware’ group was 19.68 hours as compared to 80.75 hours in the ‘Physician Unaware’ group (p=0.003) ^ For a diagnosis of no-SA or coagulase negative staphylococcus, the mean duration of empiric therapy was 35.65 hours in the ‘Physician Aware’ group as compared to 44.38 hours in the ‘Physician Unaware’ group (p=0.07). However, when treatment was considered a categorical variable and after exclusion of all cases where anti-MRS therapy was used for unrelated conditions, only 20 of 72 cases in the ‘Physician Aware’ group received treatment as compared to 48 of 106 cases in the ‘Physician Unaware’ group. ^ Conclusions. Earlier diagnosis of MRSA may not alter final treatment outcomes. However, earlier identification may lead to the earlier institution of measures to limit the spread of infection. The early diagnosis of MSSA infection, does lead to treatment with specific antibiotic therapy at an earlier stage of treatment. Also, the duration of empiric therapy is greatly reduced by early diagnosis. The early diagnosis of coagulase negative staphylococcal infection leads to a lower rate of unnecessary treatment for these infections as they are commonly considered contaminants. ^

An interactive intervention to impact adherence to antiretroviral treatment among treatment-naive HIV-infected adults in Thailand: A pilot randomized controlled study

Background. Consistent adherence to antiretroviral treatment is necessary for a treatment success. Improving and maintaining adherence rate >95% are challenging for health care professionals. This pilot randomized controlled study aimed to evaluate the impact of the interactive intervention on adherence to GPO-VIR, to describe the feasibility of the interactive intervention in Thailand, and to illustrate the adherence self-efficacy concept among HIV treatment-naïve patients in Thailand who were starting antiretroviral treatment. ^ Methods. The study took place at three HIV clinics located in Phayao, Thailand. Twenty-three patients were randomly assigned into the experimental (n=11) and the control groups (n=12). Each participant in the experimental group and a significant person to the patient received 5 educational sessions with a nurse at the clinics and at their homes. They also received 3 follow-up evaluations during the 6-month period of the study. The participants in the control group received the standard of care provided by HIV clinical personnel plus three follow-up evaluations at the clinic. ^ Results. Seventeen patients (7 in the experimental and 10 in the control group) completed the study. The 4-day recall on the Thai ACTG Adherence Scale demonstrated adherence rate >95% for most participants from both groups. After the first measurement, no experimental group patients reporting missing ART, while one control group participant continuously skipped ART. Participants from both groups had significantly increased CD4 cell counts after the study (F(1, 15) = 29.30, p = .000), but no differences were found between two groups (F(1, 15) = .001, p = .98). Examination of the intervention showed limitations and possibilities to implement it in Thailand. Qualitative data demonstrated self-efficacy expectations, resignation and acceptance as related concepts to improve adherence outcomes. ^ Conclusions. This interactive intervention, after appropriate modifications, is feasible to apply for Thai HIV-treatment naïve patients. Because of limitations the study could not demonstrate whether the interactive intervention improved adherence to ART among HIV-treatment naïve in Thailand. A longitudinal study in a larger sample would be required to test the impact of the intervention. ^ Keyword: antiretroviral treatment, adherence, treatment-naïve, Thailand, randomized controlled study ^

Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8+ cytotoxic T lymphocyte responses

The specific mechanisms underlying the varied susceptibility of HIV-infected (HIV+) individuals to opportunistic infections (OI) are still incompletely understood. One hypothesis is that quantitative differences in specific T cell responses to a colonizing organism determine the development of an AIDS-defining OI. We evaluated this hypothesis for herpes simplex virus (HSV) infection, a common OI in HIV+ patients. Using limiting dilution analyses, the frequency of HSV-specific CD8+ cytotoxic T lymphocyte precursors (pCTL) and proliferative precursors were quantitated in peripheral blood mononuclear cells from 20 patients coinfected with HIV and HSV-2. The frequency of HSV-specific CD8+ pCTL in HSV+HIV+ individuals was significantly lower than in HSV+HIV− individuals (1 in 77,000 vs. 1 in 6,000, P = .0005) and was not different than in HSV-HIV− individuals (1 in 100,000, P = .24). HIV+ patients who suffered more severe genital herpes recurrences had significantly lower HSV-specific CD8+ pCTL frequencies than those patients with mild recurrences (1 in 170,000 vs. 1 in 26,000, P = .03). In contrast, no significant difference was seen in proliferative precursor frequencies between those patients with mild vs. severe genital herpes (1 in 3,800 vs. 1 in 6,600, P > .5). Quantitative differences in pCTL frequency to HSV appear to be the most important host factor influencing the frequency and severity of HSV reactivation in HIV+ patients. Studies to reconstitute such immunity, especially in people with acyclovir-resistant HSV, appear warranted.

Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure

Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36–52 weeks of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.

Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials

Objective: To determine whether preventive treatment for tuberculosis in adults infected with HIV reduces the frequency of tuberculosis and overall mortality.

Approaches for the vaccination and treatment of Neospora caninum infections in mice and ruminant models.

Neospora caninum is a leading cause of abortion in cattle, and is thus an important veterinary health problem of high economic significance. Vaccination has been considered a viable strategy to prevent bovine neosporosis. Different approaches have been investigated, and to date the most promising results have been achieved with live-attenuated vaccines. Subunit vaccines have also been studied, and most of them represented components that are functionally involved in (i) the physical interaction between the parasite and its host cell during invasion or (ii) tachyzoite-to-bradyzoite stage conversion. Drugs have been considered as an option to limit the effects of vertical transmission of N. caninum. Promising results with a small panel of compounds in small laboratory animal models indicate the potential value of a chemotherapeutical approach for the prevention of neosporosis in ruminants. For both, vaccines and drugs, the key for success in preventing vertical transmission lies in the application of bioactive compounds that limit parasite proliferation and dissemination, without endangering the developing fetus not only during an exogenous acute infection but also during recrudescence of a chronic infection. In this review, the current status of vaccine and drug development is presented and novel strategies against neosporosis are discussed.

Dually Active HIV/HBV Antiretrovirals Protect Against Incident Hepatitis B Infections: Potential for Prophylaxis.

BACKGROUND  Hepatitis-B virus (HBV) has a detrimental effect on HIV natural course, and HBV vaccination is less effective in the HIV infected. We examine the protective effect of dually active antiretroviral therapy (DAART) for HIV/HBV (Tenofovir/Lamivudine/Emtricitabine) in a large cohort encompassing heterosexuals, men-who-have-sex-with-men (MSM), and intravenous drug users (IDU), who are HIV-infected yet susceptible to HBV, with comprehensive follow-up data about risky behavior and immunological profile. METHODS  We defined an incident HBV infection as the presence of any of HBV serological markers (HBsAg/AntiHBc/HBV-DNA) following a negative baseline AntiHBc test. Patients with positive AntiHBs were excluded. Cox proportional hazard models were utilized, with an incident case of HBV infection as the outcome variable. RESULTS  We analyzed 1,716 eligible patients from the Swiss HIV Cohort Study with 177 incident HBV cases. DAART was negatively associated with incident HBV infection (hazard ratio 0.4, 95%CI 0.2-0.6). This protective association was robust to adjustment (0.3, 0.2-0.5) for condomless sex, √CD4 count, drug use, and patients' demographics. Condomless sex (1.9,1.4-2.6), belonging to MSM (2.7,1.7-4.2) or IDU (3.8,2.4-6.1) were all associated with higher HBV hazard. CONCLUSIONS  Our study suggests that DAART, independently of CD4 count and risky behavior, has a potentially strong public health impact including pre-exposure prophylaxis of HBV co-infection.