Successful Highly Active Antiretroviral Therapy Research Articles

Factors associated with immunological and virological discordant responses to highly active antiretroviral therapy among adult HIV positive individuals in Ethiopia: A cross-sectional study.

In clinical practice, not all human immune deficiency virus (HIV) positive individuals who received highly active antiretroviral therapy (HAART) achieve the desired concordant response characterized by a sustained viral suppression or immune recovery. The expected success of HAART doesn’t occur in all treated patients and a discordant response between CD4 count and the viral load (VL) has been a major concern in the treatment of HIV patients. Thus, this study is designed to describe the factors associated with immunological and virological discordant responses to HAART among adult HIV positive individuals.A hospital-based cross-sectional study with secondary data review was conducted on 423 HIV positive individuals on HAART from February 1 to April 30, 2017. Socio-demographic characteristics, clinical data and about 10 mL of blood specimen for HIV VL, and CD4 count measurement were collected. The data was entered into SPSS version 20 and descriptive, bivariate, and multivariate logistic regression analysis was employed.The mean age of the patients at study time was 39 (±9.8). The average follow-up duration of patients on antiretroviral therapy (ART) was 7 (±3) years. The prevalence of immunological discordance and virological discordance to HAART were 13.2% and 47%, respectively. With multivariate logistic regression analysis duration of follow-up on ART ≤ 6 years (adjusted odds ratio [AOR] = 3.29 (1.80–6.03), P ≤ .001) and VL ≥20 copies/mm3 (AOR = 3.08 [1.70–5.61], P ≤ .001) were significant factors for immunological discordance conversely the patients who switched drug as a result of TB (AOR = 3.33 [1.10–10.08], P = .03) was significant factors for virological discordance.The prevalence of immunological discordance and virological discordance to HAART among HIV patients is high. Patients with the duration of follow-up on ART ≤ 6 years, VL ≥ 20 copies/mm3 and patients who switched drugs as a result of TB were significant factors for discordance. Hence, intensive adherence support and counseling should be provided to achieve the UNAIDS 90 target. HIV positive individuals co-infected with TB, who have had VL ≥ 20 copies/mm3 and who are ≤6 years duration of follow-up on ART need to be carefully monitored. In addition, national based study of discordant groups is recommended.

Sexually transmitted infections among women living with HIV in a Brazilian city

BackgroundClinical improvements following highly active antiretroviral therapy (HAART) may increase high-risk behaviors resulting in sexually transmitted infections (STI). Optimism related to the success of HAART in slowing disease progression, reducing viral load, and improving health status might be important factors for increasing sexual risk behaviors such as less use of condoms. ObjectiveTo determine the prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis, hepatitis B and C, high-risk HPV, and cervical cytological abnormalities among women living with HIV (WLHIV) who attended a Reference Center for STI/AIDS in Brazil. MethodsA cross-sectional study was conducted among 151 WLHIV attending an STI Clinic in Vitória city, Brazil. A structured questionnaire, including demographic, behavioral, and clinical information, was used for data collection. Serological tests for HIV, syphilis, hepatitis C and B, CD4 counts, and viral load determination were performed. Cervical samples were collected for cytology and real-time PCR for HPV,Chlamydia, and Neisseria gonorrhoeae. ResultsIn this study, 59% of women had at least one diagnosed STI at the time of the first clinic visit; 31% had clinical forms of anogenital HPV, 10% syphilis, 8%Neisseria gonorrhoeae, 5.0% trichomoniasis, 3% Chlamydia trachomatis, 1% hepatitis B, and 1% hepatitis C; 6.7% of the women presented with cervical cytological abnormalities. Furthermore, 46.3% of women had HR-HPV, and 17.6% had HPV 16/18. Only 5% of the women had a CD4 count <200 cells/mm3, 61.6% had undetectable HIV viral load, and 81.3% were currently on HAART. ConclusionA high prevalence of STI and HR-HPV infections were observed among HIV-infected women in this investigation. Prevention programs need to focus on counseling WLHIV and their regular partners with focused interventions such as couples counseling and education programs.

FACTORS ASSOCIATED WITH QUALITY OF LIFE AMONG PEOPLE LIVING WITH HIV/AIDS ON HIGHLY ACTIVE ANTI RETROVIRAL THERAPY: A CROSS-SECTIONAL STUDY

Objective: To assess Quality of life (QoL) and its associated factors in people living with HIV/AIDS (PLWHA) who taking highly active antiretroviral therapy (HAART) in Wangaya Hospital in Denpasar, Bali, Indonesia.&#x0D; Methods: A cross-sectional study was conducted during February 2019 to January 2020 at Wangaya Hospital in Denpasar, Bali, Indonesia. QoL was assessed using the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L), EQ-5D index value, and the EuroQol visual analogue scale (EQ-VAS). The data was analyzed using Statistical Package for Social Science (SPSS) software package version 26.0. Bivariate analysis was tested using the cross-tabulation Gamma, Kruskal-Wallis and post hoc Mann-Whitney test. P value&lt;0.05 was considered as statistically significant.&#x0D; Results: A total of 584 PLWHA took HAART for at least 3 mo. The median index value and EQ-VAS were 1.0 (range-0.514–1.0) and 100.00 (range 30-100), respectively. Most patients had problems in ‘anxiety/depression’ and ‘pain/discomfort’ domains. Predictors of better QoL included men, married, good adherence, and treatment duration&gt;24 mo (p&lt;0.05). Predictor of poorer QoL included an advanced HIV clinical stage(p=0.001).&#x0D; Conclusion: The QoL scores of PLWHA receiving HAART in our study were high; hence the QoL of PLWHA was good. The good QoL can be taken as the goal for HIV treatment in order to have a successful HAART therapy.

Immunological Response During HAART and Determinants of Current CD4+ T-Cell Count Among HIV/AIDS Patients Attending University of Gondar Referral Hospital, Northwest Ethiopia.

PurposeAfter the initiation of highly active antiretroviral therapy (HAART), successful HAART is characterized by an increase in the CD4+ count. Several factors affect the CD4+ T-cell count. This study aimed to assess the immunological response during HAART and determinants of the current CD4+ T-cell count among HIV/AIDS patients on HAART.Patients and MethodsA hospital-based cross-sectional study was conducted from February 1 to April 1, 2017. A total of 423 HIV/AIDS patients on HAART were enrolled using simple random sampling. Descriptive statistics, and bivariate and multiple regression analyses were conducted. Variables with p-value <0.2 in the bivariate analysis were entered in the multiple regression models. p-Values <0.05 and 95% confidence intervals were used to identify determinants of the current CD4+ T-cell count.ResultsThe mean CD4+ T-cell count gradually increased until 8 years on HAART but declined thereafter. An increased current CD4+ T-cell count was observed among patients with an initial regimen of pediatric d4T-3TC-NVP [β=185.5, 95% CI (8.8, 362.2)] (p=0.040), with increased baseline CD4+ T-cell count [β=0.468, 95% CI (0.342, 0.594)] (p<0.0001), and with long duration on HAART [β=18.0, 95% CI (9.9, 26.1)] (p<0.0001), whereas a decreased level of current CD4+ T-cell count was observed among males [β=−72.7, 95% CI (−114.5, –30.9)]) (p<0.0001) and those with poor baseline adherence [β=−108.9, 95% CI (−210.9, −7.0)] (p=0.036) and viral load >1000 copies [β=−189.2, 95% CI (−243.5, −134.9)] (p<0.0001).ConclusionThe trend in immunological response was not increased linearly throughout the HAART duration. Sex, type of initial regimen, baseline adherence, baseline CD4+ count, viral load, and duration on HAART were independent determinants of current CD4+ count. These determinants could be addressed by regular monitoring of HIV patients on HAART, and special attention should be paid to male patients.

Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression.

Chronic HIV infection results in a loss of HIV-specific CD8(+) T cell effector function, termed "exhaustion," which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8(+) T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8(+) T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions. Despite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.

Impact of therapeutic drug monitoring of antiretroviral drugs in routine clinical management of patients infected with human immunodeficiency virus and related health care costs: a real-life study in a large cohort of patients.

BackgroundHighly active antiretroviral therapy (HAART) has reduced morbidity and mortality in patients infected with human immunodeficiency virus (HIV). Studies have documented high interindividual variability in the pharmacokinetics of antiretroviral drugs, which may impair the success of HAART if not managed properly. Therapeutic drug monitoring (TDM) is a useful diagnostic tool that helps clinicians to optimize drug doses so that drug concentrations associated with the highest therapeutic efficacy are obtained with a reduced risk of concentration-dependent adverse effects. The aim of this study was to assess whether use of TDM improves clinical outcomes and cost of illness.MethodsA retrospective cohort study was conducted at L Sacco University Hospital in Milan, Italy, in HIV-infected patients aged ≥18 years with at least one prescription of antiretroviral drugs for which TDM was applied. The inclusion period was from January 2010 to December 2011, with a follow-up period of up to 12 months. Laboratory and administrative databases were analyzed and matched with each other.ResultsThe cohort consisted of 5,347 patients (3,861 males and 1,486 females) of mean age 43.9±12.5 years. We found that TDM had been used in 143 of these patients, among whom adherence with therapy was significantly higher than among those in whom TDM had not been used (94% versus 78%). In TDM-controlled patients, the mean length of HIV-related hospitalization stay and mean cost of hospitalization were significantly reduced with respect to those observed in the group in which TDM had not been used (7.21 days versus 29.47 days and €293 versus €688, respectively).ConclusionInclusion of TDM as part of routine clinical optimization of drug dosing in HIV-infected patients is associated with higher adherence to therapy, reduced length of hospitalization stay, and reduced cost of illness.

HIV DNA and Immune Alteration During Successful HAART

Highly Active Antiretroviral therapy (HAART) can effectively reduce the viral load to undetectable levels in most HIV-infected patients. However, some patients may still experience impaired immunologic response associated with increased risk of disease progression and death. The objective of this study was to assess the impact of the HIV DNA load on the immune alteration during successful HAART. 40 chronic HIV-infected adults initiating HAART were followed for 24 months. The CD4 count, HIV viral load, HIV DNA load, and levels of γ-cytokines IL-2, IL-7 and IL-21 were monitored at baseline (month 0), month 6, 12, 18 and 24 following HAART initiation. The plasma viral load decreased significantly and remained below the detection limits after six months treatment. Likely the HIV DNA load decreased significantly in both cells during 12 months, was undetectable in CD14 monocytes after 18 months, but remained higher in CD3+ T cells during all the follow up. In addition, the HIV DNA load correlated positively between T cells and monocytes in 10 patients who maintained higher HIV DNA load in both cells during 12 months. The CD4 count, IL-2, and IL-21 levels increased significantly during 12 months, whereas IL-7 decreased significantly during 18 months, regardless of the HIV DNA load in T cells. Patients with CD4 count below 200/μl maintained higher HIV DNA load and showed lower increase in CD4 count compared to patients with CD4 count above 200/μl. In patients showing undetectable HIV DNA load in both cells, neither IL-2 nor IL-21 correlated with the CD4 count even after 24 months despite their partial restoration. These results suggest that the HIV DNA load could continuously hamper the CD4 restoration and γ-cytokines functional activities during HAART. This action seemed to be more severe in patients with pre-HAART CD4 count below 200/μl. The CD14 monocytes may contribute to this action as source of T cell infection both before and during HAART.

Central memory CD4 T cells are associated with incomplete restoration of the CD4 T cell pool after treatment-induced long-term undetectable HIV viraemia

It is unclear to what extent T cell reconstitution may be possible in HIV-1-infected individuals on continuous successful highly active antiretroviral therapy (HAART). Herein, we analysed distinct phenotypic markers of immune recovery in patients with undetectable viraemia for 8 years, taking as reference untreated patients and healthy controls. Seventy-two subjects were examined: 28 HIV-1+ patients on successful long-term HAART, 24 HIV-1+ untreated viraemic patients and 20 age-matched healthy controls. Analysis of naive and memory CD4 and CD8 T cells was combined with measurements of activation status (expression of CD38) and with thymic function (expression of CD31). Statistical significance was determined by non-parametric tests. After long-term HAART, the majority of parameters were normalized compared with age-matched control values, including T cell activation and thymic function. However, absolute counts of naive and central memory CD4 T cells remained below normal levels. The only parameters significantly associated with CD4 counts at the end of follow-up were the pre-HAART CD4 count ( β ± SD = 0.54 ± 0.16, P = 0.003) and the level of CD4 central memory cells at the end of follow-up (β ± SD = 1.18 ± 0.23, P < 0.0001). Only patients starting HAART with CD4 counts >350 cells/mm(3) reached a complete normalization of CD4 counts. Even after long-term successful HAART, complete CD4 restoration may be attainable only in patients starting therapy with moderately high CD4 counts, prompting early initiation of antiretroviral therapy. Incomplete CD4 restoration may be associated with a defective restoration of central memory CD4 T cells, a cell subset with a pivotal role in T cell homeostasis.

Current progress in the development of RNAi-based therapeutics for HIV-1

Highly active antiretroviral therapy (HAART) treatment for HIV has changed the course of AIDS in societies in which the drugs are readily available. Despite the great success of HAART, drug resistance and toxicity issues still remain a concern for some individuals. Thus, a number of investigators have been exploring other approaches for inhibiting HIV-1 replication. One of the most potent of these is the use of RNA interference (RNAi). This review will focus solely on the use of RNAi for the treatment of HIV-1 infection, including the problems, progress and future prospects.

AIDS-Related Pathology

AIDS-Related Pathology

Impact of Non-HIV and HIV Risk Factors on Survival in HIV-Infected Patients on HAART: A Population-Based Nationwide Cohort Study

BackgroundWe determined the impact of three factors on mortality in HIV-infected patients who had been on highly active antiretroviral therapy (HAART) for at least one year: (1) insufficient response to (HAART) and presence of AIDS-defining diseases, (2) comorbidity, and (3) drug and alcohol abuse and compared the mortality to that of the general population.Methodology/Principal FindingsIn a Danish nationwide, population-based cohort study, we used population based registries to identify (1) all Danish HIV-infected patients who started HAART in the period 1 January 1998–1 July 2009, and (2) a comparison cohort of individuals matched on date of birth and gender (N = 2,267 and 9,068, respectively). Study inclusion began 1 year after start of HAART. Patients were categorised hierarchically in four groups according to the three risk factors, which were identified before study inclusion. The main outcome measure was probability of survival from age 25 to 65 years. The probability of survival from age 25 to age 65 was substantially lower in HIV patients [0.48 (95% confidence interval (CI) 0.42–0.55)] compared to the comparison cohort [0.88 (0.86 to 0.90)]. However, in HIV patients with no risk factors (N = 871) the probability of survival was equivalent to that of the general population [0.86 (95% CI 0.77–0.92)]. In contrast, the probability of survival was 0.58 in patients with HIV risk factors (N = 704), 0.30 in patients with comorbidities (N = 479), and 0.03 in patients with drug or alcohol abuse (N = 313).ConclusionsThe increased risk of death in HIV-infected individuals is mainly attributable to risk factors that can be identified prior to or in the initial period of antiretroviral treatment. Mortality in patients without risk factors on a successful HAART is almost identical to that of the non–HIV-infected population.

Progressive multifocal leukoencephalopathy in an HIV patient receiving successful long-term HAART

Progressive multifocal leukoencephalopathy (PML) has been traditionally associated to severe immunosuppression and described mainly in highly active antiretroviral therapy (HAART)-naïve patients with a low lymphocyte CD4+ count. In the last years, some cases of PML have been described in HIV patients with a higher CD4+ count shortly after initiation of HAART and in association with the immune reconstitution inflammatory syndrome (IRIS). We report on a rare case of PML, not IRIS associated, that occurred in a HIV-positive patient with a lymphocyte CD4+ count greater than 700/µl and with an undetectable HIV viral load resulting from a long-term HAART. We describe the pathological and the ultrastructural features of the brain lesion. This case confirms that a severe immunosuppression or an IRIS is not required for the development of PML in HIV positives. The diagnosis of PML should always be considered in patients with consistent neurological symptoms, even with a high lymphocyte CD4+ level and a full viral suppression resulting from a long-term HAART.

Risk management in HIV/AIDS: ethical and economic issues associated with restricting HAART access only to adherent patients

Like many other developing nations, South Africa faces the challenge of mobilising resources in response to the HIV pandemic. There is a large budget gap between the ideal and the actual amount of funding needed to achieve universal access to highly active antiretroviral therapy (HAART). In addition to financial demands, new burdens are being placed on HAART programmes with the emergence of HIV drug resistance (HIVDR). Thus, a major threat to successful HAART rollout is HIVDR due to non-adherence to HAART. The use of HAART as a primary and secondary HIV-prevention strategy could be ineffective in situations characterised by high rates of non-adherence. In this context, the research looked at issues related to adherence and non-adherence to HAART from the perspective of the provider. Using the software TreeAge Pro 2009, we developed a Markov model to project economic outcomes for a hypothetical cohort of HIV/AIDS patients on HAART. The model compared two scenarios: adherence and non-adherence to HAART. Input data for the model was obtained from existing literature on HAART uptake in South Africa. Moral arguments were analysed and managed through moral reasoning and critical thinking. Discounted lifetime costs for adherent and non-adherent HAART patients in South Africa were estimated at US$9 771 and US$14 762, respectively. The model showed the loss of 4.55 quality-adjusted life years (QALYs) for non-adherent patients, which could be otherwise gained through improved adherence. The incremental cost-effectiveness ratio (ICER) indicated that restricting HAART access only to adherent patients was the dominant strategy. We suggest that, although not a panacea, the withholding or withdrawal of treatment from non-adherent individuals as a precautionary intervention has economic and moral merit.

Mode of delivery in HIV-infected pregnant women and prevention of mother-to-child transmission: changing practices in Western Europe.

The aim of the study was to examine temporal and geographical patterns of mode of delivery in the European Collaborative Study (ECS), identify factors associated with elective caesarean section (CS) delivery in the highly active antiretroviral therapy (HAART) era and explore associations between mode of delivery and mother-to-child transmission (MTCT). The ECS is a cohort study in which HIV-infected pregnant women are enrolled and their infants prospectively followed. Data on 5238 mother-child pairs (MCPs) enrolled in Western European ECS sites between 1985 and 2007 were analysed. The elective CS rate increased from 16% in 1985-1993 to 67% in 1999-2001, declining to 51% by 2005-2007. In 2002-2004, 10% of infants were delivered vaginally, increasing to 34% by 2005-2007. During the HAART era, women in Belgium, the United Kingdom and the Netherlands were less likely to deliver by elective CS than those in Italy and Spain [adjusted odds ratio (AOR) 0.07; 95% confidence interval (CI) 0.04-0.12]. The MTCT rate in 2005-2007 was 1%. Among MCPs with maternal HIV RNA<400 HIV-1 RNA copies/mL (n=960), elective CS was associated with 80% decreased MTCT risk (AOR 0.20; 95% CI 0.05-0.65) adjusting for HAART and prematurity. Two infants born to 559 women with viral loads <50 copies/mL were infected, one of whom was delivered by elective CS (MTCT rate 0.4%; 95% CI 0.04-1.29). Our findings suggest that elective CS prevents MTCT even at low maternal viral loads, but the study was insufficiently powered to enable a conclusion to be drawn as to whether this applies for viral loads <50 copies/mL. Diverging mode of delivery patterns in Europe reflect uncertainties regarding the risk-benefit balance of elective CS for women on successful HAART.

Enhanced HIV Testing, Treatment, and Support for HIV-Infected Substance Users

Enhanced HIV Testing, Treatment, and Support for HIV-Infected Substance Users

Preparing for highly active antiretroviral therapy rollout in rural South Africa: an assessment using the information, motivation, and behavioral skills model

Following a controversial history and before South Africa started the world's largest highly active antiretroviral therapy (HAART) rollout, little was known about community-level information, motivation, and behavioral skills (IMB) regarding HAART in high-HIV-prevalence rural communities. The IMB model has been shown to predict behaviors that are associated with desirable HAART outcomes. We conducted an anonymous, cross-sectional “HAART-Felt Prospects” survey among HIV-serostatus-unknown young adults in Tugela Ferry, KwaZulu-Natal. We aimed to identify behavioral aspects of HAART preparedness that could be targeted by local interventions to enhance HAART outcomes. Data analysis included: percent correct, thematic means based on a four-point Likert-scale, and composite quotients. Subjects (N=176) were Zulu (99%), young (mean 19 years), and severely impoverished (55%). Relatively high levels of information were reported: overall correct score was 46%, secondary-transmission-of-resistance information was highest (81%), and only 15% reported traditional or government-advocated folk remedies cure or treat HIV/AIDS. Motivation quotient was “consistent” with favorable HAART behaviors; attitudes toward medication-taking behaviors (3.48) and condom use during HAART (3.43) ranked the highest. Desire for HIV testing (71%) was associated with HIV treatment optimism [adjusted odds ratio (AOR)=4.0, p=0.0004] and previous experience with good treatment outcome [AOR=3.2, p=0.01]. Acceptance of HAART (93%) was associated with HIV optimism [AOR=18.0, p=0.001] and not believing government-advocated folk remedies cure or treat HIV/AIDS [AOR=10.0, p=0.04]. Behavioral skills quotient was “neutral” for favorable HAART behaviors; side effects self-efficacy was the highest (3.16); and medication-taking self-efficacy the lowest (2.51). Only 47% believed disclosing HIV-serostatus would be easy. Despite controversy surrounding HAART initiation, these results suggest that local South African at-risk youth were relatively well-poised for HAART rollout. This conclusion is supported by subsequent successful HAART rollout locally. Community-based assessments are urgently needed as HAART rollouts continue. Adaptation of this IMB-based survey may better inform efforts to enhance HAART-program implementation in resource-limited settings globally.

Social and structural determinants of HAART access and adherence among injection drug users

Highly active antiretroviral therapy (HAART) has dramatically improved health outcomes among people living with HIV/AIDS. However, significant rates of HIV-related morbidity and mortality have persisted among HIV-positive injection drug users (IDU) globally. To date, research as well as programmatic and policy responses have failed to adequately address barriers to HAART access and adherence among IDU both in developing/transitional and developed countries. A review of existing literature suggests that this is due to a shortage of context-specific evidence and an overemphasis on individual-level and behavioural variables. We propose a conceptual shift away from understanding suboptimal HAART adherence as determined predominantly by individual factors modifiable through individually focused interventions, towards a greater acknowledgement of the influence of social and structural factors such as stigmatization and social exclusion, unstable housing environments, the organization of health care systems and the continued prohibitionist approach to illicit drug policy. Globally, the future of a successful HAART treatment approach for HIV-positive IDU relies largely on a more careful consideration of these social and structural barriers that IDU face and, importantly, on a serious commitment to effect social and structural changes that will foster conditions which allow IDU to enjoy the full benefits of HAART.

Liver disease: the effects of HIV and antiretroviral therapy and the implications for early antiretroviral therapy initiation

With the advent of highly active antiretroviral therapy (HAART), end-stage liver disease has emerged as a major cause of death in HIV and hepatitis-coinfected patients. With the recent change of guidelines recommending early HAART for the treatment of HIV in hepatitis B or C-coinfected patients, the question arises how these recommendations are substantiated by existing data. In the following review, we discuss current data on the effects of HAART in the context of concurrent hepatitis B and C infection. Virologically successful HAART slows the progression of liver fibrosis and downregulates liver inflammation in hepatitis-coinfected patients. Indeed, cohort studies demonstrate a reduction in liver disease-related death events in HAART-treated patients. Moreover, the rate of immune reconstitution under HAART has been shown to determine the risk for future hepatic decompensation. Early HAART clearly proves to be beneficial for hepatitis-coinfected patients, and concerns on an increased risk for drug-related liver injury should not be a reason to withhold HAART.

Idiopathic AIDS Enteropathy and Treatment of Gastrointestinal Opportunistic Pathogens

Diarrhea in patients with acquired immune deficiency syndrome (AIDS) has proven to be both a diagnostic and treatment challenge since the discovery of the human immunodeficiency virus (HIV) virus more than 30 years ago. Among the main etiologies of diarrhea in this group of patients are infectious agents that span the array of viruses, bacteria, protozoa, parasites, and fungal organisms. In many instances, highly active antiretroviral therapy remains the cornerstone of therapy for both AIDS and AIDS-related diarrhea, but other targeted therapies have been developed as new pathogens are identified; however, some infections remain treatment challenges. Once identifiable infections as well as other causes of diarrhea are investigated and excluded, a unique entity known as AIDS enteropathy can be diagnosed. Known as an idiopathic, pathogen-negative diarrhea, this disease has been investigated extensively. Atypical viral pathogens, including HIV itself, as well as inflammatory and immunologic responses are potential leading causes of it. Although AIDS enteropathy can pose a diagnostic challenge so too does the treatment of it. Highly active antiretroviral therapy, nutritional supplementation, electrolyte replacements, targeted therapy for infection if indicated, and medications for symptom control all are key elements in the treatment regimen. Importantly, a multidisciplinary approach among the gastroenterologist, infectious disease physician, HIV specialists, oncology, and surgery is necessary for many patients.