Development Of Antiretroviral Therapy Research Articles

Molecular Study of HIV-Tat Aggregation

Despite major advancements in development of antiretroviral therapy, currently there is no effective treatment to block the impact of HIV-Tat protein which is released extracellularly and can cause activation of lymphocytes, glial cells and neurotoxicity. Because the structure of extracellular Tat is currently unknown, we used atomic force microscopy, circular dichroism and computer simulation to study the structure and aggregation characteristics of HIV-Tat protein. We found that about 8% of the HIV-Tat population was in monomeric state, the rest being in aggregated state. The aggregates ranged in size from dimers, trimers, tetramers to large oligomers (50-mers and larger) and all structures presented a globular shape. Circular dichroism measurements suggested that 20% of the sample's structure is alpha-helical, which likely represents the aggregated state, since monomers were few. The reducing agent dithiothreitol broke down the large aggregates, leading to a population of smaller aggregates, but structures smaller than the monomer were found as well, indicating that the molecule is prone to rupture under reducing conditions. CuSO4 induced dimerization and larger aggregates of HIV-Tat. A change of 14-19 aminoacids in protein structure, including the Cys 31 replacement with Ser led to a larger number of monomers in the sample (11%), a distribution of smaller aggregates, and reduced adherence to mica. Freezing of Tat reduced the aggregates size, increased their adherence capacity and ruptured the molecule. Further studies will investigate the effect of protein concentration, solution ionic strength, temperature variation and time of storage in solution, to characterize the aggregated state and its reversibility.

A broad spectrum anti-HIV inhibitor significantly disturbs V1/V2 domain rearrangements of HIV-1 gp120 and inhibits virus entry

Inhibition of human immunodeficiency virus (HIV) entry into target human cells is considered as a critical strategy for preventing HIV infection. Conformational shifts of the HIV-1 envelope glycoprotein (gp120) facilitates the attachment of the virus to target cells, therefore gp120 remains an attractive target for antiretroviral therapy development. Compound 18A has been recently identified as a broad-spectrum anti-HIV inhibitor. It was proposed that 18A disrupts rearrangements of V1/V2 region in gp120; however, the precise mechanism by which 18A interferes with the inherent motion of V1/V2 domain remains obscure. In this report, we elaborate on the binding mode of compound 18A to the closed conformation of a soluble cleaved gp120 and further examine the dynamic motion of V1/V2 region in both gp120 and the gp120–18A complex via all-atom molecular dynamics simulations. In this work, comparative molecular dynamic analyses revealed that 18A makes contact with Leu179, Ile194, Ile424, Met426 W427, E370 and Met475 in the main hydrophobic cavity of the unliganded gp120 and disrupts the restructuring of V1/V2 domain observed in apo gp120. The unwinding of α1 and slight inversion of β2 in gp120 leads to the shift of VI/V2 domain away from the V3 N-terminal regions and toward the outer domain. Stronger contacts between Trp425 and Trp112 rings may contribute to the reduced flexibility of α1 observed upon 18A binding thereby inhibiting the shifts of the V1/V2 region. Binding of 18A to gp120: (1) decreases the overall flexibility of the protein and (2) inhibits the formation a gp120 conformation that closely ressembles a CD4-bound-like conformation. Information gained from this report not only elaborates on important dynamic features of gp120, but will also assist with the future designs of potent gp120 inhibitors as anti-HIV.

The Impact of Different CD4 Cell-Count Monitoring and Switching Strategies on Mortality in HIV-Infected African Adults on Antiretroviral Therapy: An Application of Dynamic Marginal Structural Models.

In Africa, antiretroviral therapy (ART) is delivered with limited laboratory monitoring, often none. In 2003–2004, investigators in the Development of Antiretroviral Therapy in Africa (DART) Trial randomized persons initiating ART in Uganda and Zimbabwe to either laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). CD4 cell counts were measured every 12 weeks in both groups but were only returned to treating clinicians for management in the LCM group. Follow-up continued through 2008. In observational analyses, dynamic marginal structural models on pooled randomized groups were used to estimate survival under different monitoring-frequency and clinical/immunological switching strategies. Assumptions included no direct effect of randomized group on mortality or confounders and no unmeasured confounders which influenced treatment switch and mortality or treatment switch and time-dependent covariates. After 48 weeks of first-line ART, 2,946 individuals contributed 11,351 person-years of follow-up, 625 switches, and 179 deaths. The estimated survival probability after a further 240 weeks for post-48-week switch at the first CD4 cell count less than 100 cells/mm3 or non-Candida World Health Organization stage 4 event (with CD4 count <250) was 0.96 (95% confidence interval (CI): 0.94, 0.97) with 12-weekly CD4 testing, 0.96 (95% CI: 0.95, 0.97) with 24-weekly CD4 testing, 0.95 (95% CI: 0.93, 0.96) with a single CD4 test at 48 weeks (baseline), and 0.92 (95% CI: 0.91, 0.94) with no CD4 testing. Comparing randomized groups by 48-week CD4 count, the mortality risk associated with CDM versus LCM was greater in persons with CD4 counts of <100 (hazard ratio = 2.4, 95% CI: 1.3, 4.3) than in those with CD4 counts of ≥100 (hazard ratio = 1.1, 95% CI: 0.8, 1.7; interaction P = 0.04). These findings support a benefit from identifying patients immunologically failing first-line ART at 48 weeks.

L’infection par le VIH : une maladie chronique redéfinissant la collaboration entre généralistes et spécialistes. Obstacles et opportunités

With the development of antiretroviral therapy, Human Immunodeficiency Virus [HIV) infection has become a chronic disease. In order to develop an efficient response to this new challenge, there is a need for closer collaboration between specialized units and general practitioners. This article identifies the opportunities for and the barriers to this collaboration. Semi-structured interviews were conducted with patients living with HIV, general practitioners working in multidisciplinary group practice using the capitation system and infectiologists from one Belgian urban area. Interviews focused one xperiences and expectations in relation to diagnosis, follow-up and collaboration between general practitioners and infectiologists. Overall, infectiologists and general practitioners aspire to improved communication and collaboration. There are overlaps between general practitioner's and infectiologist's field of action. The general practitioner's intervention is sometimes restricted to common uncomplicated or psychosocial problems, in the context of unplanned and short contacts.Infectiologists prefer to focus on HIV problems, leaving general practitioners to take care of these patients' other health problems. The patient may be an obstacle to greater involvement of general practitioners due to fear of stigmatization from his family and social circle or lack of confidence in the general practitioner's skills. This research underlines the difficulties and gaps in the care of HIV patients and provides preliminary explanations for the lack of active cooperation between general practitioners and infectiologists. Overlaps between the areas of professional skills can result in uncovered aspects of care, which can have a negative impact on patients, but also on general practitioners and infectiologists. Collaboration between general practitioners and infectiologists should be based on a concerted decision, with clear allocation of tasks, taking into account the patient's expectations.

Management of lipid disorders in patients living with HIV.

Since the discovery and development of antiretroviral therapy (ART), HIV has become a chronic disease with patients living longer lives and to ages where co-morbidities, such as cardiovascular disease (CVD) are prevalent. Diagnosis and management of risk factors for CVD, in particular dyslipidemia, have become an important part of the overall care for patients living with HIV infection. Existing guidelines and recommendations for the management of dyslipidemia for persons with HIV infection are largely based on guidelines for the general population. Clinical and epidemiologic research efforts are ongoing to provide information specific to patients living with HIV. This review offers a detailed guide for clinicians who manage dyslipidemia in patients infected with HIV. The first sections provide background information on dyslipidemia, risk stratification, and targets for lipid therapy. This is followed by a step-by-step approach for diagnosis and treatment with specific information on lipid drug use for patients with HIV. The recommendations presented here are based on existing guidelines for the general population, evidence from research in patients infected with HIV, and the clinical experience of the authors. Management issues for which little or no information is available specific to this patient population are noted and serve to highlight the many gaps in our knowledge that will need to be addressed.

HIV Prevention and Treatment Fields Join Forces

There remains no doubt that the development of antiretroviral therapy (ART) for the prevention and treatment of HIV infection has been one of the greatest medical advancements in the past few decades. When those without HIV use ART appropriately as either pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), HIV acquisition is almost universally prevented (Grant et al., 2010). Similarly, when those with HIV use therapy appropriately, transmission to others rarely if ever occurs (Cohen et al., 2011), and the risk of developing AIDS is completely eliminated.

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy

In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.

Mitochondrial toxicities of nucleoside analogue reverse transcriptase inhibitors in AIDS cases

The development of antiretroviral therapy (ART) has been one of the most dramatic progressions in the history of medicine. Concomitant with this momentous therapeutic advance, the mitochondrial toxicities of ART were recognized as an important clinical entity.Aim:The aim was to study the mitochondrial toxicities in terms of peripheral neuropathy (PN), lipodystrophy (LD), hepatic steatosis, lactic academia (LA), and pancreatitis developing in AIDS cases on nucleoside analog reverse transcriptase inhibitors (NRTIs) based ART regimens.Materials and Methods:An observational study, which included 90 AIDS cases, receiving first line ART regimens containing two NRTIs (zidovudine [AZT]/stavudine [d4T] with lamivudine [3TC]) and one nonNRTIs (nevirapine/efavirenz) was conducted at Skin-VD outpatient department of a tertiary care hospital attached to a Medical College. Thorough history was taken, and clinical examination was done. Cases were subjected to measurements of abdominal girth and mid-arm circumference, liver function tests, blood sugar, lipid profile, serum lactate, and amylase levels.Results:Of 90 cases on ART, 66% were males and 34% were females. Mitochondrial toxicities developed in 26 (30%) cases out of 90, which included 3 (7%) out of 42 cases on AZT + 3TC and 23 (48%) out of 48 cases on d4T + 3TC. Most common toxicity was PN seen in 20 (22%) cases; male cases developed PN at a lower CD4 count than female cases. LD was observed in total of 13 (14.5%) cases; deposition of fat in the abdomen in seven cases and at the nape of the neck (buffalo hump) in one case while loss of fat from extremities was seen in seven cases and loss of buccal fat in seven cases. Women presented more with fat accumulation (breast and abdomen), while men with loss of fat (limbs and buttocks). Both PN and LD were more common in d4T based regimen. LA was reported in one case on d4T. Hepatic steatosis was seen in three cases and pancreatitis in one case receiving AZT.Conclusion:Regular monitoring and early diagnosis of mitochondrial toxicities with timely switch to safer alternatives is of utmost importance.

Economics and HIV: the sickness of economics by Deborah Johnston, and: South African AIDS Activism and Global Health Politics by Mandisa Mbali (review)

Reviewed by: Economics and HIV: the sickness of economics by Deborah Johnston, and: South African AIDS Activism and Global Health Politics by Mandisa Mbali Alan Whiteside (bio) Deborah Johnston ( 2013) Economics and HIV: the sickness of economics. London: Routledge Mandisa Mbali ( 2013) South African AIDS Activism and Global Health Politics. Basingstoke: Palgrave MacMillan There are numerous articles and books on the HIV/AIDS epidemic. In writing this review I carried out a quick scan of new social science books with the words HIV and AIDS in the titles. I identified seven from main stream publishers in 2012 and six up to mid-2013 (including the titles reviewed here). Readers and scholars, unless they are autodidacts, need to be selective about what they read. These two books look at the economics of the pandemic at the global scene level and global politics and South African activism respectively. Interestingly both remark on the need for more research in order to understand the issues they address. The point, which neither makes, is we need deeper, nuanced research not simply more. Mbali’s book is developed from her PhD. This documents and interprets the history of AIDS activism from its beginnings to about 2004, five years after the establishment of the Treatment Action Campaign (TAC) (there is a useful postscript that takes the story up to about 2011). She examines the responses to the AIDS from the emergence of the epidemic in 1982. She goes on to describe political transitions, the changing role of TAC and the development and growth in international alliances. The book is in two parts: ‘AIDS activism and South Africa’s transition’ and ‘the TAC and global health politics’. Johnston sets out a critical review of the work of economists especially [End Page 141] in relation to their perspective on disease. Her book is neatly divided into two parts each with four chapters. The first section comprises chapters looking at ‘The economics of HIV transmission: fads and fashions’, the second part is ‘The economic impact of AIDS: the past, the present and the future’. The opening chapter asks if economics and HIV/AIDS is a failed opportunity, and she ends with advocating for a new approach to economics. Both books tell stories of disappointment. In the case of Mbali she addresses the inability of government to respond appropriately to the greatest public health and development challenge faced by the state. Johnston considers her discipline to have botched the issue, stating in her preface: ‘Economics has largely failed to provide useful insights on the HIV/AIDS pandemic. The inability of a dominant branch of social science to assist in understanding an illness with significant social, economic and emotional effects is a serious failing in its own right’. Mbali’s analysis is strongest when looking at the evolution of the TAC and understanding how it built global alliances. The key moments were the emergence and rapid spread of HIV; the development of Anti-retroviral therapy in 1996; the establishment of the TAC in 1998 to advocate for treatment, including prevention of mother to child transmission, which at that point in the epidemic, was fairly simple to provide; the government’s unwillingness to provide this and indeed any treatment; the court case where the administration took on the pharmaceutical industry and won the right to provide cheaper generic medicine; and finally the Mbeki denial of the efficacy of drugs and ultimately his questioning the existence of HIV. This book might be described as the biography of the TAC. It is written by someone who was intimately involved with the organisation in its critical early years. It is perceptive and, at times, passionate. It is an output of a PhD, and as such is to be applauded. As Mbali grows as a scholar her work and analysis should deepen. There are, in this book, many pointers to directions she could take. One example is describing the emergence of AIDS as ‘coincidental’ with ‘the dying days of apartheid’. This needs to be thought through more carefully. Johnston’s book would help her in understanding the reasons for the spread of epidemic as being more than coincidence. Both authors have activist, feminist and leftist backgrounds and...

Mitochondrial toxicities of nucleoside analogue reverse transcriptase inhibitors in AIDS cases.

The development of antiretroviral therapy (ART) has been one of the most dramatic progressions in the history of medicine. Concomitant with this momentous therapeutic advance, the mitochondrial toxicities of ART were recognized as an important clinical entity. The aim was to study the mitochondrial toxicities in terms of peripheral neuropathy (PN), lipodystrophy (LD), hepatic steatosis, lactic academia (LA), and pancreatitis developing in AIDS cases on nucleoside analog reverse transcriptase inhibitors (NRTIs) based ART regimens. An observational study, which included 90 AIDS cases, receiving first line ART regimens containing two NRTIs (zidovudine [AZT]/stavudine [d4T] with lamivudine [3TC]) and one nonNRTIs (nevirapine/efavirenz) was conducted at Skin-VD outpatient department of a tertiary care hospital attached to a Medical College. Thorough history was taken, and clinical examination was done. Cases were subjected to measurements of abdominal girth and mid-arm circumference, liver function tests, blood sugar, lipid profile, serum lactate, and amylase levels. Of 90 cases on ART, 66% were males and 34% were females. Mitochondrial toxicities developed in 26 (30%) cases out of 90, which included 3 (7%) out of 42 cases on AZT + 3TC and 23 (48%) out of 48 cases on d4T + 3TC. Most common toxicity was PN seen in 20 (22%) cases; male cases developed PN at a lower CD4 count than female cases. LD was observed in total of 13 (14.5%) cases; deposition of fat in the abdomen in seven cases and at the nape of the neck (buffalo hump) in one case while loss of fat from extremities was seen in seven cases and loss of buccal fat in seven cases. Women presented more with fat accumulation (breast and abdomen), while men with loss of fat (limbs and buttocks). Both PN and LD were more common in d4T based regimen. LA was reported in one case on d4T. Hepatic steatosis was seen in three cases and pancreatitis in one case receiving AZT. Regular monitoring and early diagnosis of mitochondrial toxicities with timely switch to safer alternatives is of utmost importance.

Influence of adding etravirine on complexity index and patients' perceived complexity

Adherence to highly active antiretroviral treatment (HAART) is an important predictive factor of treatment outcome. Medication regimen complexity can be one of the main causes of non-adherence. Thus, treatment simplification is a key strategy in the development of antiretroviral therapy. The aim of this study was to determine the influence of adding etravirine on complexity index and patients' perceived complexity of their treatment regimen. We conducted a prospective two-centre observational study. Patients on etravirine-based therapy, for at least 6months, who came personally to pharmacy departments for a drug refill from February to July 2012 were included. Data were collected for the current etravirine-based HAART and for the previous HAART without etravirine. The main variables were complexity index and patients' perceived complexity. We also evaluated the adherence during the 6months before and after the introduction of etravirine into HAART. The complexity index was based on a score which takes into account the number of pills per day, the dosing schedule, the dosage form and any specific instructions linked to use of the drug. To evaluate the patients' perceived complexity of their current and previous HAART, patients were asked to assign a mark on a visual analogue scale ranging from 0 (minimum) to 10 (maximum). We assessed the differences in the variables collected between the current and previous antiretroviral therapy. Finally, we carried out a correlation analysis between the complexity index and the patients' perceived complexity. Eighty patients were included. The complexity index was significantly reduced after the addition of etravirine to HAART (P=0·035). Perceived complexity was also reduced (P=0·015). After the introduction of the drug, the proportion of adherent patients increased from 65% to 81·3% (P=0·002). The correlation between the complexity index and the patients' perceived complexity was positive (r=0·594). The correlation increased (r=0·696) when the difference between the complexity index before and after the introduction of etravirine in HAART grew. The addition of etravirine to HAART results in a significant reduction in complexity index and patients' perceived complexity of their therapy. These changes were associated with better adherence to treatment.

Deenan Pillay: virologist in HIV's heartlands

Deenan Pillay: virologist in HIV's heartlands

Aging with HIV: a practical review

The worldwide elderly population is expected to grow by an additional 694 million people by 2025. By that time, there will be approximately two billion elderly people in the world, most of whom (80%) will be living in developing countries. Based on recent estimates, this population will number over 40 million in 2030 in Brazil and a consequent increase in governmental spending for this population can be expected. Since highly active antiretroviral therapy became available in the mid-1990s, the life expectancy of people living with HIV has increased significantly. Approximately 12 million life years were added to the world between 1996 and 2008 as a consequence of wider access to highly active antiretroviral therapy. In Brazil, the incidence of AIDS among the population aged ≥50 years doubled between 1996 and 2006. The development of antiretroviral therapy has allowed individuals diagnosed at a younger age to live longer, which partially explains the aging tendency associated with the HIV/AIDS epidemic. It is estimated that by 2015, subjects aged ≥50 years will represent 50% of the people living with HIV undergoing clinical treatment. This scenario presents some challenges, including the fact that the diagnosis of HIV tends to be delayed in older patients compared to younger patients because the symptoms of HIV can be confused with those of other common diseases among the elderly and also because healthcare professionals do not consider this population to be at high risk for HIV infection. In regard to the individuals diagnosed with HIV, a further challenge is presented by the morbidity normally associated with aging. Finally, the elderly also exhibit higher susceptibility to the toxic effects and pharmacological interactions of medications. The present article reviews the literature regarding the profile of HIV infection among individuals aged ≥50 years focusing on practical features related to the clinical approach and long-term follow-up of this population.

Detection of anti-tat antibodies in CSF of individuals with HIV-associated neurocognitive disorders

Despite major advances in the development of antiretroviral therapies, currently available treatments have no effect on the production of HIV-Tat protein once the proviral DNA is formed. Tat is a highly neurotoxic and neuroinflammatory protein, but its effects may be modulated by antibody responses against it. We developed an indirect enzyme-linked immunosorbent assay and measured anti-Tat antibody titers in CSF of a well characterized cohort of 52 HIV-infected and 13 control individuals. We successfully measured anti-Tat antibodies in CSF of HIV-infected individuals with excellent sensitivity and specificity, spanning a broad range of detection from 10,000 to over 100,000 relative light units. We analyzed them for relationship to cognitive function, CD4 cell counts, and HIV viral load. Anti-Tat antibody levels were higher in those without neurocognitive dysfunction than in those with HIV-associated neurocognitive dysfunction (HAND) and in individuals with lower CD4 cell counts and higher viral loads. We provide details of an assay which may have diagnostic, prognostic, or therapeutic implications for patients with HAND. Active viral replication may be needed to drive the immune response against Tat protein, but this robust immune response against the protein may be neuroprotective.

Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial.

Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)-recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0-4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12-38) months. From mothers' ART, 62/9/111 infants had no/20%-89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75-212) days. Overall, 14 infants died at median (IQR) age 9 (3-23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. Overall 1-year 5% infant mortality was similar to the 2%-4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children. www.controlled-trials.com ISRCTN13968779

The Current State of HIV Vaccine Research

Copyright: © 2012 Varela M . This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The development of a vaccine against HIV is a global health priority and a tremendous scientific challenge that has been hampered by the extraordinary genetic diversity of HIV and the immune evasive properties of the HIV envelope glycoprotein to which neutralizing antibodies target. In 2006, Robert Gallo commented: “...if AIDS had to come, we were lucky (scientifically speaking) it came at a very good time” [1]. He referred to the accumulated knowledge on the retroviral replication cycle and the modern tools in molecular biology that were developed in the seventies which became available in the eighties when HIV was discovered. Although the HIV/AIDS epidemics came at a “good time”, HIV has proven to be unique in its transmission, pathogenesis and replication, hampering the way to the discovery of a vaccine and effective therapy. It is unquestionable that the tools, resources and international effort invested to prevent HIV infection and end the global pandemic is unprecedented in the history of infectious agents. Despite the development of antiretroviral therapy that can extend the life of infected individuals, these drugs are not widely available in the underdeveloped world and, thus, a therapeutic vaccine would be of great benefit. Unfortunately, traditional vaccination approaches have failed to confer protection and, thus, complex and rational antigen design approaches have been proposed. These have also proven in most cases ineffective when tested in pre-clinical vaccine trials in nonhuman primates. There are multiple reasons why it has been so difficult to develop a protective vaccine. From the virus perspective, the extreme genetic diversity within and between hosts with the presence of distinct clades affecting different parts of the world, along with circulating recombinant forms, complicates the design of antigens that can provide protection across different subtypes. From the host point of view, it is still not clear which are the responses that should be developed to confer protection. And from the experimental point of view, which is the best animal model for pre-clinical trials. The bottom line is that we find ourselves 30 years after HIV was discovered under the light of just a single phase III trial were modest protection was observed [2]. Luckily, as scientists we are not convinced that the raw results of this trial and all the downstream analysis including the dissection of the immune correlates of protection, or the investigation of the breakthrough viral population, among others, will provide all the answers needed to generate the ultimate antigen and immunization strategy that will contain this pathogen. We should take this trial as a new beginning to re-evaluate, think and question antigens, strategies and protocols, but most importantly, to help accelerate the advance of candidates into the clinics. This special issue gathers several articles going from antigen development to HIV animal models that aim at updating the current state of HIV vaccine research. Has HIV come at a good time? We still can turn the answer around.

Does Antiretroviral Therapy Improve HIV-Associated Cognitive Impairment? A Quantitative Review of the Literature

The development of antiretroviral therapy (ART) has dramatically improved survival for those living with human immunodeficiency virus (HIV), but whether ART improves cognitive functioning remains unclear. The aim of the present review was to examine systematically the extent to which ART improves cognition among individuals with HIV using meta-analytic methods. Twenty-three studies were included in the quantitative review. ART was associated with modest improvements in attention (mean d = .17; p < .001; 95% confidence interval [CI], .09/.25), executive function (mean d = .18; p < .001; 95% CI, .10/.26), and motor function (mean d = .24; p < .001; 95% CI, .16/.32). ART did not improve language, verbal memory, visual memory or visuospatial function. The extent to which cognition improved was correlated with the change in CD4 cell count following ART, suggesting a link between cognitive outcome and immune system integrity. Together, the present findings indicate that the neuropsychological test performance of most HIV patients taking ART is comparable to those not taking ART. Development of pharmaceutical treatments and rehabilitation strategies that target the cognitive effects of HIV infection is needed.

The charms and challenges of antiretroviral therapy in Uganda: the DART experience

Antiretroviral therapy (ART) improves the quality of life of people living with HIV/AIDS. However, adherence remains a challenge. A total of eight focus group discussions (FGD) were conducted with participants from a randomised controlled trial that monitored strategies for managing ART in African adults: Development of Antiretroviral Therapy. All FGD participants had received ART for at least one year. Perceived benefits of ART were key motivators for adherence. These benefits included improved physical health, restored self-esteem, acceptance in the community and hope for a longer and healthier life and reduced fear of HIV/AIDS-related death. Barriers to adherence included a high pill burden, ART side effects and socio-economic constraints, including lack of food and safe water for taking the pills. Visible ART side effects and involvement in an exclusively HIV/AIDS clinic could expose their HIV status, thus exacerbating stigma. Gender and socio-economic differences were found in the variety of strategies employed to ensure adherence. ART was perceived as improving the overall quality of life of recipients; however, it is crucial for ART programmes to be gender and socio-economic cognizant in order to enhance adherence to a lifelong therapy.

158 HIV-1 Matrix Protein p17: A Candidate Antigen for Therapeutic Vaccines Against AIDS

The success in the development of anti-retroviral therapies (HAART) that contain Human Immunodeficiency Virus type 1 (HIV-1) infection are challenged by the cost of this lifelong therapy and by its toxicity. Immune-based therapeutic strategies that boost the immune response against HIV-1 proteins or protein subunits have been recently proposed to control virus replication in order to provide protection from disease development, reduce virus transmission, and help limit the use of anti-retroviral treatments. HIV-1 matrix protein p17 is a structural protein that is critically involved in most stages of the life cycle of the retrovirus. Besides its well established role in the virus life cycle, increasing evidence suggests that p17 may also be active extracellularly in deregulating biological activities of many different immune cells that are directly or indirectly involved in AIDS pathogenesis. Thus, p17 might represent a promising target for developing a therapeutic vaccine as a contribution to combating AIDS. Here we discuss the biological characteristics of HIV-1 matrix protein p17 and describe why a synthetic peptide representative of the p17 functional epitope may work as a vaccine molecule capable of inducing anti-p17 neutralizing response against p17 derived from divergent HIV-1 strains.

Clustering based on adherence data

Adherence to a medical treatment means the extent to which a patient follows the instructions or recommendations by health professionals. There are direct and indirect ways to measure adherence which have been used for clinical management and research. Typically adherence measures are monitored over a long follow-up or treatment period, and some measurements may be missing due to death or other reasons. A natural question then is how to describe adherence behavior over the whole period in a simple way. In the literature, measurements over a period are usually combined just by using averages like percentages of compliant days or percentages of doses taken. In the paper we adapt an approach where patient adherence measures are seen as a stochastic process. Repeated measures are then analyzed as a Markov chain with finite number of states rather than as independent and identically distributed observations, and the transition probabilities between the states are assumed to fully describe the behavior of a patient. The patients can then be clustered or classified using their estimated transition probabilities. These natural clusters can be used to describe the adherence of the patients, to find predictors for adherence, and to predict the future events. The new approach is illustrated and shown to be useful with a simple analysis of a data set from the DART (Development of AntiRetroviral Therapy in Africa) trial in Uganda and Zimbabwe.