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Archive for the ‘what I read’ Category

what I read, and what I don’t – Monday, July 30 2007

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On Monday, July 30 2007, I read that the NYT criticizes Republican congressional leaders who have attacked the proposed expansion of the State Children’s Health Insurance Program (SCHIP), a bipartisan initiative that would increase the number of insured children from low-income families. Republican “leaders may be on message at the White House, where President Bush is foolishly threatening a veto,” but they they “seem way off message for the American public and even their own party caucuses,” the editors write …

What I don’t read is, that there are some 462.430 children were born with no medical insurance since the actual 110th Congress commenced work. The number is increasing by one child in less than one minute’s time 24/7.  Watch the clock at I don’t read either, that actually in 2006 overall 6,9 million minors did benefit from this biggest public health initiative since the Medicaid-Programme in the sixties.

On the same day I read, that the WaPo also criticizes Republicans for blocking efforts to boost the number of low-income children who receive health insurance. The editors note that while Republicans say they “want to concentrate on enrolling poor children” in health insurance programs, they “fail to provide enough money to do so effectively.” Do “House Republicans really want to be arguing for taking away health insurance from children who now have it?” the editors ask …  

What I don’t read is, that the Bush administration plans on 30 Mio. USD for the following 5 years, whereas the first 10 years did cost 40 Mio. USD, while deputies and experts estimate 50 Mio. USD necessary to maintain the momentary insurance situation. Convincing as those figures are for national economists, I want to hear one parent among deputies using them to argue against medical assistance for his own child.

Like the discussion were not about children’s access to necessary healthcare – we are not discussing subsidies to Ben&Jerry’s icecream production – I read that asthmatic children profiting from medical assistance regularly, are 70% less likely to have an attack and need 60% less medical consultations.

I read, that President Bush said he would veto the Schip expansion bill on “philosophical” grounds. That is scary. When did GWB put hands on philosophy, and “what kind of philosophy says that it’s O.K. to subsidize insurance companies, but not to provide health care to children?”, as NYT columnist Paul Krugman is asking. The way the president presented himself so far, makes the problem even more dangerous. What has he put hands on altogether, as he is hardly able to tell what philosophy is in fact?

Ironically enough, if Bush expresses his veto and his party offers even token support, it might be better for children benefiting from the programme as well as for those left outside. Democratic sweep in 2008 would be then even more likely, after all the Iraqui-war “successes” recently presented to the public; they would bring with them a mandate for serious reform — universal coverage, simplified reimbursement, first-dollar coverage for preventive and chronic care…

Written by huehueteotl

September 12, 2007 at 2:35 pm

Infection With HIV-2 Or HIV-1 – What Is The Difference?

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There are two distinct, but related, HIV viruses that humans can become infected with — HIV-1 and HIV-2. Individuals infected with HIV-2 progress to AIDS at a dramatically reduced rate compared with individuals infected with HIV-1; in fact, most individuals infected with HIV-2 die of unrelated causes.

It is hoped that understanding why individuals infected with HIV-2 rarely progress to AIDS will help with the design of therapeutics and vaccine strategies for the treatment and prevention, respectively, of infection with HIV-1.

A new study by Aleksandra Leligdowicz and colleagues at the Weatherall Institute of Molecular Medicine, Oxford, demonstrates that individuals infected with HIV-2 mount a strong immune response to a specific region of the viral protein Gag.

The robustness of this response was inversely correlated with the amount of virus detected in the individual. In turn, individuals with high levels of detectable virus had fewer CD4+ T cells, indicating that they were progressing towards AIDS. The authors therefore suggest that T cell responses to Gag are important in determining the better outcome of infection with HIV-2 than infection with HIV-1.

J Clin Invest. 2007 Sep 6; [Epub ahead of print]

Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection.

Leligdowicz A, Yindom LM, Onyango C, Sarge-Njie R, Alabi A, Cotten M, Vincent T, da Costa C, Aaby P, Jaye A, Dong T, McMichael A, Whittle H, Rowland-Jones S.

Medical Research Council Laboratories, Fajara, Republic of The Gambia. Weatherall Institute of Molecular Medicine, Medical Research Council Human Immunology Unit, John Radcliffe Hospital, Oxford, United Kingdom. Projecto Saude Bandim, Bissau, Republic of Guinea-Bissau.

HIV-2 infection in the majority of infected subjects follows an attenuated disease course that distinguishes it from infection with HIV-1. Antigen-specific T cells are pivotal in the management of chronic viral infections but are not sufficient to control viral replication in HIV-1-positive subjects, and their function in HIV-2 infection is not fully established. In a community-based cohort of HIV-2 long-term nonprogressors in rural Guinea-Bissau, we performed what we believe is the first comprehensive analysis of HIV-2-specific immune responses. We demonstrate that Gag is the most immunogenic protein. The magnitude of the IFN-gamma immune response to the HIV-2 proteome was inversely correlated with HIV-2 viremia, and this relationship was specifically due to the targeting of Gag. Furthermore, patients with undetectable viremia had greater Gag-specific responses compared with patients with high viral replication. The most frequently recognized peptides clustered within a defined region of Gag, and responses to a single peptide in this region were associated with low viral burden. The consistent relationship between Gag-specific immune responses and viremia control suggests that T cell responses are vital in determining the superior outcome of HIV-2 infection. A better understanding of how HIV-2 infection is controlled may identify correlates of effective protective immunity essential for the design of HIV vaccines.

Written by huehueteotl

September 12, 2007 at 11:40 am

Posted in HIV, what I read

Personal Chaos In HIV Patients’ Lives May Be A Barrier To Regular Medical Care

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Pharmindustry lately seems to love funding research about bad HIV guys, who do not take their pills regularly. I assume, it is because those guys ruin the last bits of ROI that can be squeezed out of market in the Western world. That same industry is ways less interested in AIDS-related health issues in what is called the Third World. These studies do find out everytime so amazing things! This time we learn, that unstable and unpredictable lifestyles are significant factors in determining access to health care among low-income HIV-positive people, from a new UCLA study.

The study mirculously found that when HIV patients lead chaotic lives — meaning they are disorganized or experience too many unexpected events — that chaos can act as a barrier to regular medical care. The ingenious researchers even tailored a new scale to gauge the level of chaos in an adult’s life (in case you wanna try?).

The findings suggest a possible new alternative to help ensure that low-income patients get the care they need, said the study’s lead author, Dr. Mitchell Wong, an assistant professor of general internal medicine and health services research at the David Geffen School of Medicine at UCLA. (The study also finds interesting odds concerning racial provenance among participants. But these were less likely to be leading to “new help alternatives” and hence are amiss in the discussion of results.)

“Many people have barriers to care, such as problems with transportation, housing, child care and health insurance. Traditionally, we look to solve these problems with case managers who can help reduce these barriers,” Wong said. “But there’s a whole potential other mechanism which might be happening — that people are just having trouble managing and organizing their lives. I think many of us take for granted the support mechanisms that we have, but many people who are living in poverty don’t have that support network. They don’t have that buffer zone to cope with the unexpected things. Perhaps enhancing stability and organization in people’s lives can also help them get the regular care that they need.”

Some 220 low-income HIV-positive patients participated in the study. Of those, 45 percent were African American, 40 percent were Latino and 20 percent were women. About one-third did not graduate from high school, approximately 75 percent had a history of homelessness and half had used drugs in the previous 30 days. In addition, 45 percent were uninsured and 75 percent had one or more unmet social-service need. In the six months prior to the study, 83 percent had seen a physician for HIV care at least twice, 46 percent missed two or more visits, and one-third had gone to a hospital emergency room at least once.

In developing the new scale to measure chaos in adults’ lives, the researchers took as their model the 15-item Confusion, Hubbub, and Order Scale (CHAOS), designed for parents to assess chaos affecting children’s home lives. The researchers changed some questions in the CHAOS scale to reflect a person’s life in general and whittled the assessment down to six simple statements designed to key in on the level of chaos in patients’ lives. These statements had a five-point response ranging from “strongly agree” to “strongly disagree.”

The statements were:

  • My life is organized.
  • My life is unstable.
  • My routine is the same from week to week.
  • My daily activities from week to week are unpredictable.
  • Keeping a schedule is difficult for me.
  • I do not like to make appointments too far in advance because I do not know what might come up.

The researchers found that those patients who did not have spouses or partners and those with at least one unmet social-service need, such as transportation or housing, scored highest on the chaos scale.

They also found that patients with more chaos in their lives were less likely to have had two or more outpatient HIV care visits and were more likely to have missed two or more visits in the six months prior to enrolling in the study. These patients also had lower mental health status, both when they enrolled in the survey and at follow-up. The researchers, however, did not find an association between life chaos and emergency department visits or physical health status.

The Health Resources and Services Administration, the National Institute on Aging, the Pfizer Foundation, the National Center on Minority Health and Health Disparities, and the National Institute of Mental Health funded the study.

J Gen Intern Med. 2007 Sep;22(9):1286-91. Epub 2007 Jun 28.

The association between life chaos, health care use, and health status among HIV-infected persons.

Wong MD, Sarkisian CA, Davis C, Kinsler J, Cunningham WE.

UCLA Division of General Internal Medicine and Health Services Research, University of California, 911 Broxton Avenue, Suite 101, Los Angeles, CA 90024, USA.

BACKGROUND: Whether having a stable and predictable lifestyle is associated with health care use and health status among HIV patients is unknown. OBJECTIVE: To develop and test the reliability and validity of a measure of life chaos for adults with HIV and examine its association with health care use and health status. DESIGN: Prospective cohort study. PARTICIPANTS: Two hundred twenty HIV-infected persons recruited from those who tested positive in a mobile testing van and from HIV clinics serving low-income populations. MEASUREMENTS: Participants completed a survey every 6 months, assessing their health care use, SF-12 mental and physical health status and life chaos. RESULTS: Cronbach’s alpha for the six-item measure of chaos was .67. Those without a spouse or partner and those with one or more unmet social service needs, such as housing or transportation, had higher chaos scores. Compared to those with less chaos, those with more chaos were less likely to have two or more outpatient visits (adjusted odds ratio [OR] 0.48, 95% confidence interval [CI]: 0.24-0.98), more likely to have two or more missed visits (adjusted OR 2.30, 95%CI: 1.20-4.41) in the 6 months before study enrollment and had lower mental health status at enrollment and at follow-up. Life chaos was not associated with emergency department visits or physical health status. CONCLUSIONS: We created a new measure of life chaos, which was associated with outpatient visits and mental health status. Chaos may be an important barrier to regular medical care. Future studies need to test this measure in more diverse populations and those with other diseases.

Written by huehueteotl

September 12, 2007 at 11:21 am

Posted in HIV, what I read

Virological Evidence Can NOT Prove Transmission In HIV Criminal Cases

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Virological evidence cannot prove transmission in HIV criminal cases, warn experts in the British Medical Journal.

Viral phylogenetics provides a way of assessing the relations between viruses from different people. It allows us to estimate the probability that viruses from two particular people have a recent common origin. But there are serious limitations on what can and cannot be inferred using this technique.

The recent flurry of criminal cases brought against people in the United Kingdom accused of infecting their sexual partner(s) with HIV has resulted in several convictions, write Professor Deenan Pillay and colleagues in an editorial.

This has caused concern amongst health professionals and community groups about the detrimental effect such cases may have on disclosure of HIV infection and uptake of voluntary HIV testing.

In some cases, attempts have been made to present evidence on HIV viral sequence data in a similar way to DNA fingerprinting.

In our view, this analogy is seriously misleading, say the authors. When attempting to establish that transmission occurred between specific people, virological evidence should be used with caution and only in conjunction with the clinical and epidemiological evidence.

The greatest difficulty lies with the nature of the data, they write. Identifying a link between viruses from two people on its own says nothing about who infected whom. Other difficulties include the unlikelihood that all sexual contacts of all HIV infected people will be available for viral testing, co-infection with genetically diverse strains, and similarities in two virus genomes as a result of convergent or parallel evolution.

They advise caution when interpreting such data because the strength of any apparent linkage between viruses will never approach the degree of certainty generally expected of DNA data in a criminal court.

Phylogenetic evidence — together with clinical and epidemiological evidence regarding likely duration of infection, sexual history, and other relevant factors — can provide support for linkage between cases but cannot prove transmission, they say.

Despite the difficulty in determining linkage between specific individuals, phylogenetics can provide important new insights in investigations, they say. A recent example is a study of the timing of HIV-1 infections among Libyan children in hospital, which showed that most infections occurred before the arrival of the accused medical workers in the country.

It will be important that sufficient checks and balances are in place to allow full use of HIV surveillance data for public health benefit, without concern that the underlying purpose for identifying possible viral genetic linkage between people will be to support criminal proceedings, they conclude.

BMJ  2007;335:460-461 (8 September), doi:10.1136/bmj.39315.398843.BE

HIV phylogenetics

Criminal convictions relying solely on this to establish transmission are unsafe

Deenan Pillay, Andrew Rambaut, Anna Maria Geretti, and Andrew J Leigh Brown
No Abstract availabe – the first 150 words of the full text of this article appear below.

The recent flurry of criminal cases brought against people in the United Kingdom accused of infecting their sexual partner(s) with HIV has resulted in several convictions. This has caused concern among health professionals and community groups about the detrimental effect such cases may have on disclosure of HIV infection and uptake of voluntary HIV testing, which contrasts with the move to normalise HIV testing and clinical care. The potential negative effect of this on the public health programme to reduce transmission of HIV has been widely discussed in these pages1 2 and elsewhere.3

Virological evidence, specifically HIV gene sequence data obtained from the defendant and complainant, has been used in these cases because a prerequisite for establishing criminal liability is that the defendant caused the complainant’s infection. Because HIV-1, like other RNA viruses, evolves rapidly, the virus isolated from independently infected people is typically distinct. The extent of similarity between viruses . . . [Full text of this article]

Written by huehueteotl

September 11, 2007 at 11:32 am

Posted in HIV, what I read

So AIDS Is Not About Losing Helper Cells …

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… as it appears in three related papers, providing new insights into the complexity of HIV/AIDS.

Don Sodora, Ph.D., a principal investigator in SBRI’s Viral Vaccines Program who recently joined SBRI from the University of Texas, Southwestern Medical Center, is senior author on one of three papers that collectively show CD4 T-cell depletion, a critical symptom of AIDS, is likely a part of a multifaceted scenario that triggers disease rather than the only cause.

In an HIV-infected person, CD4 T-cells (white blood cells that play a central role in creating immunity) decline and, at a certain point, the person gets sick and dies. This rapid and dramatic loss of CD4 T-cells is considered to be a key determinant of AIDS disease. However, in natural hosts, like the sooty mangabey (an African monkey species), simian immunodeficiency virus (SIV) induced CD4 T-cell depletion can be comparable to that in humans, but the monkeys do not show clinical signs of AIDS. “Our assessment of these natural hosts like mangabeys offers insight into the disease and shows us that progression to AIDS likely results from the cumulative effects of HIV/SIV replication, CD4 T-cell depletion, generalized immune activation and non-CD4 T-cells depletion or dysfunction,” said Sodora.

Sodora’s paper provides evidence, using the sooty mangabey SIV natural host, that virally induced CD4 T-cell depletion, by itself, is not sufficient to induce AIDS in a natural host. “When we first observed the dramatic CD4 depletion in all the tissues we examined in these monkeys, we were concerned that they might begin to exhibit clinical signs of AIDS,” said Jeffrey Milush, Ph.D., lead author on the paper. “But after more than six years, we are sure that CD4 depletion by itself does not necessarily result in progression to AIDS”.

Sodora contributed to a second paper, with senior author Guido Silvestri, M.D., of the University of Pennsylvania. In a study of disease free SIV–infected sooty mangabeys, Silvestri proposes that these African monkeys preserve immune function despite a major loss of mucosal CD4 T-cells as a result of an evolutionary adaptation to reduce immune activation in response to virus replication.

The third of the three papers published this week in The Journal of Immunology, with Ivona Pandrea, M.D., Ph.D., and Cristian Apetrei, M.D., Ph.D., from Tulane University as lead authors, shows that a severe loss of intestinal CD4 T-cells in another natural host, the African green monkey, is also not predictive of SIV virulence.

“These three papers published together indicate that CD4 T-cell depletion is one part of a more complex scenario that results in the clinical signs identified as AIDS,” Sodora said. “We hope that studies in these natural host models will lead to improved HIV vaccines or new therapeutics that might someday make HIV-infected people more like these disease-resistant sooty mangabeys.”

J Immunol. 2007 Sep 1;179(5):3047-56.

Virally Induced CD4+ T Cell Depletion Is Not Sufficient to Induce AIDS in a Natural Host.

Milush JM, Reeves JD, Gordon SN, Zhou D, Muthukumar A, Kosub DA, Chacko E, Giavedoni LD, Ibegbu CC, Cole KS, Miamidian JL, Paiardini M, Barry AP, Staprans SI, Silvestri G, Sodora DL.

University of Texas Southwestern Medical Center, Dallas, TX 75390.

Peripheral blood CD4(+) T cell counts are a key measure for assessing disease progression and need for antiretroviral therapy in HIV-infected patients. More recently, studies have demonstrated a dramatic depletion of mucosal CD4(+) T cells during acute infection that is maintained during chronic pathogenic HIV as well as SIV infection. A different clinical disease course is observed during the infection of natural hosts of SIV infection, such as sooty mangabeys (Cercocebus atys), which typically do not progress to AIDS. Previous studies have determined that SIV(+) mangabeys generally maintain healthy levels of CD4(+) T cells despite having viral replication comparable to HIV-infected patients. In this study, we identify the emergence of a multitropic (R5/X4/R8-using) SIV infection after 43 or 71 wk postinfection in two mangabeys that is associated with an extreme, persistent (>5.5 years), and generalized loss of CD4(+) T cells (5-80 cells/mul of blood) in the absence of clinical signs of AIDS. This study demonstrates that generalized CD4(+) T cell depletion from the blood and mucosal tissues is not sufficient to induce AIDS in this natural host species. Rather, AIDS pathogenesis appears to be the cumulative result of multiple aberrant immunologic parameters that include CD4(+) T cell depletion, generalized immune activation, and depletion/dysfunction of non-CD4(+) T cells. Therefore, these data provide a rationale for investigating multifaceted therapeutic strategies to prevent progression to AIDS, even following dramatic CD4 depletion, such that HIV(+) humans can survive normal life spans analogous to what occurs naturally in SIV(+) mangabeys.

J Immunol. 2007 Sep 1;179(5):3026-34.

Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys.

Gordon SN, Klatt NR, Bosinger SE, Brenchley JM, Milush JM, Engram JC, Dunham RM, Paiardini M, Klucking S, Danesh A, Strobert EA, Apetrei C, Pandrea IV, Kelvin D, Douek DC, Staprans SI, Sodora DL, Silvestri G.

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.

HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4(+) T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4(+) T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4(+) T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4(+) T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4(+) T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS.

J Immunol. 2007 Sep 1;179(5):3035-46.

Acute Loss of Intestinal CD4+ T Cells Is Not Predictive of Simian Immunodeficiency Virus Virulence.

Pandrea IV, Gautam R, Ribeiro RM, Brenchley JM, Butler IF, Pattison M, Rasmussen T, Marx PA, Silvestri G, Lackner AA, Perelson AS, Douek DC, Veazey RS, Apetrei C.

Divisions of Comparative Pathology and Microbiology, Tulane National Primate Research Center, Covington, LA 70433.

The predictive value of acute gut-associated lymphoid tissue (GALT) CD4(+) T cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of SIV infection: pathogenic infection (SIVsmm infection of rhesus macaques (Rh)), persistent nonprogressive infection (SIVagm infection of African green monkeys (AGM)), and transient, controlled infection (SIVagm infection of Rh). Massive acute depletion of GALT CD4(+) T cells was a common feature of acute SIV infection in all three models. The outcome of this mucosal CD4(+) T cell depletion, however, differed substantially between the three models: in SIVsmm-infected Rh, the acute GALT CD4(+) T cell depletion was persistent and continued with disease progression; in SIVagm, intestinal CD4(+) T cells were partially restored during chronic infection in the context of normal levels of apoptosis and immune activation and absence of damage to the mucosal immunologic barrier; in SIVagm-infected Rh, complete control of viral replication resulted in restoration of the mucosal barrier and immune restoration. Therefore, our data support a revised paradigm wherein severe GALT CD4(+) T cell depletion during acute pathogenic HIV and SIV infections of humans and Rh is necessary but neither sufficient nor predictive of disease progression, with levels of immune activation, proliferation and apoptosis being key factors involved in determining progression to AIDS.


see also:

J Exp Med. 2007 Sep 3;204(9):2171-85. Epub 2007 Aug 27.

Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.

Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M Jr, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, Picker LJ.

Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006.

Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4(+) memory T cell proliferation appears to prevent collapse of effector site CD4(+) T(EM) cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4(+) T(EM) cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells. These data suggest that although CD4(+) T(EM) cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T(CM) cells.

Written by huehueteotl

September 11, 2007 at 11:17 am

Posted in HIV, what I read

Socioeconomic Position Associated With Effectiveness Of HIV Drugs

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Socioeconomic position is a determinant of antiretroviral treatment effectiveness during initial therapy for HIV-1 infection. The effect was found in a study from Harvard School of Public Health (HSPH), Massachusetts General Hospital, Stanford University Medical School, and the American Psychological Association, even among subjects with high rates of drug adherence, according to a study published in the August 1 issue of the Journal of Psychosomatic Research. One probably has to live in Harvard to wonder how this is possible. And one does not have to wonder that there are means for such amazing research, as the study was supported by grants from GlaxoSmithKline, Pfizer, and Novartis. In case you wonder why those companies are interested in behavioral factors influencing patient’s compliance see: with adequate profit, capital is very bold – HIV market to top $10 billion

The researchers used data from a clinical trial that recruited HIV-positive men and women in the U.S. and Italy who had not previously taken any HIV medications. The study participants were being treated with highly active antiretroviral treatment (HAART), a combination of antiretroviral drugs sometimes referred to as an AIDS “cocktail.”

Scientific literature suggests that stress and emotional distress predict a faster decline in the immune system cells that can fight HIV progression. Previous studies have shown that people at lower socioeconomic positions often report chronic life stressors. The HSPH team and its collaborators wanted to examine whether socioeconomic position would influence immune functioning and response to antiretroviral treatments, even if patients adhered to their antiretroviral drugs. The researchers used the educational level of subjects as a measure for socioeconomic position.

The study’s authors documented the length of time until a participant first experienced a regimen failure, meaning that the drug combination had failed to maintain low HIV levels in the bloodstream or that HIV drugs had been changed or stopped. The researchers found that participants with lower levels of education reached initial regimen failure faster than participants with a college- or graduate-level degree.

However, participants with high levels of so-called “adherence self-efficacy,” despite lower education levels, experienced a reduction in initial regimen failure by 15 to 17 percent. Adherence self-efficacy was described by the authors as a coping resource that reflected the strength of the patient’s belief in the effectiveness of their medication and their ability to adhere to their treatment regimen. The authors suggest that one reason behind this association may be that coping styles are known to be associated with better immune functioning in individuals with HIV disease.

“These findings support health promotion programs focusing on psychological and behavioral aspects associated with therapeutic regimens, which might not otherwise be considered in the treatment of HIV,” said Linda Marc, who led the research project while a Doctor of Science candidate in the Department of Society, Human Development, and Health at HSPH. Marc is now a lecturer at Yale School of Public Health and chair of the HIV/AIDS Special Interest Group for the International Society for Quality of Life Research.

Marc and her team also point out that the study’s results may be particularly relevant to HIV care in the developing world. However, Marc noted, it is unknown if these results can be extrapolated to resource-poor settings because the trial was conducted with participants who live in developed nations. Marc added that since little is known about the impact of stressors on immune functioning in resource-poor settings, she believes there is a need to promote research methods in these parts of the world that simultaneously examine biological and social factors.

“In this way, researchers can better understand the variations of immune functioning and determine what proportion of treatment failure is modifiable through social variables, in contrast to known biological factors of HIV treatment effectiveness,” she said.

J Psychosom Res. 2007 Aug;63(2):207-16.

Educational attainment and response to HAART during initial therapy for HIV-1 infection.

Marc LG, Testa MA, Walker AM, Robbins GK, Shafer RW, Anderson NB, Berkman LF; for the ACTG Data Analysis Concept Sheet Study Team.

Cornell HIV Clinical Trials Unit, New York, NY, USA; Department of Psychiatry, Weill Medical College of Cornell, White Plains, NY, USA; Harvard School of Public Health, Boston, MA, USA.

OBJECTIVE: Previous research has demonstrated an association between educational attainment (EA) and negative physical and psychological outcomes. This study investigated whether EA is associated with regimen failure during initial therapy with highly active antiretroviral treatment (HAART) and whether adherence self-efficacy (ASE), a coping resource, moderates the relationship between EA and regimen failure. METHODS: A secondary analysis of AIDS Clinical Trial Group Protocol 384, an international, multicenter, randomized, partially double-blinded trial, included 799 male and 181 female antiretroviral-naïve subjects (age, 37.0+/-9.5 years). Participants were recruited from 1998 to 1999 and followed for a median of 2.3 years across 81 centers. The dependent variable was “time to first regimen failure.” Covariates include baseline HIV-1 log(10)RNA and CD4(+) counts, self-reported adherence, study site, ASE, age, sex, race, treatment assignment, and baseline use of nonantiretroviral medications. RESULTS: ASE significantly moderated the relationship between EA and regimen failure. Results showed that for every 10-unit increase in ASE, individuals with “less than high school” education had a 17% reduction in regimen failure (hazard ratio=0.83; 95% confidence interval=0.70-0.98) when compared to the reference group “college/graduate,” even after adjusting for baseline factors known to contribute to regimen failure. The time to first regimen failure was shorter with decreasing EA, trending toward significance (P=.08). CONCLUSIONS: There is a social gradient in HAART effectiveness, and ASE reduces the deleterious effects of lower EA on regimen failure. We recommend designing controlled interventions to evaluate the effectiveness of programs that increase ASE prior to initiation with HAART, particularly for those with lower EA.

see also:

AIDS Behav. 2004 Jun;8(2):141-50.

Factors influencing medication adherence beliefs and self-efficacy in persons naive to antiretroviral therapy: a multicenter, cross-sectional study.

Reynolds NR, Testa MA, Marc LG, Chesney MA, Neidig JL, Smith SR, Vella S, Robbins GK; Protocol Teams of ACTG 384, ACTG 731 and A5031s.

Ohio State University, Columbus 43210, USA.

It is widely recognized that adherence to antiretroviral therapy is critical to long-term treatment success, yet rates of adherence to antiretroviral medications are frequently subtherapeutic. Beliefs about antiretroviral therapy and psychosocial characteristics of HIV-positive persons naive to therapy may influence early experience with antiretroviral medication adherence and therefore could be important when designing programs to improve adherence to antiretroviral therapy. As part of a multicenter AIDS Clinical Trial Group (ACTG 384) study, 980 antiretroviral-naive subjects (82% male, 47% White, median age 36 years, and median CD4 cell count 278 cells/mm3) completed a self-administered questionnaire prior to random treatment assignment of initial antiretroviral medications. Measures of symptom distress, general health and well-being, and personal and situational factors including demographic characteristics, social support, self-efficacy, depression, stress, and current adherence to (nonantiretroviral) medications were recorded. Associations among variables were explored using correlation and regression analyses. Beliefs about the importance of antiretroviral adherence and ability to take antiretroviral medications as directed (adherence self-efficacy) were generally positive. Fifty-six percent of the participants were “extremely sure” of their ability to take all medications as directed and 48% were “extremely sure” that antiretroviral nonadherence would cause resistance, but only 37% were as sure that antiretroviral therapy would benefit their health. Less-positive beliefs about antiretroviral therapy adherence were associated with greater stress, depression, and symptom distress. More-positive beliefs about antiretroviral therapy adherence were associated with better scores on health perception, functional health, social-emotional-cognitive function, social support, role function, younger age, and higher education (r values = 0.09-0.24, all p < .001). Among the subset of 325 participants reporting current use of medications (nonantiretrovirals) during the prior month, depression was the strongest correlate of nonadherence ( r = 0.33, p < .001). The most common reasons for nonadherence to the medications were “simply forgot” (33%), “away from home” (27%), and “busy” (26%). In conclusion, in a large, multicenter survey, personal and situational factors, such as depression, stress, and lower education, were associated with less certainty about the potential for antiretroviral therapy effectiveness and one’s perceived ability to adhere to therapy. Findings from these analyses suggest a role for baseline screening for adherence predictors and focused interventions to address modifiable factors placing persons at high risk for poor adherence prior to antiretroviral treatment initiation.

Written by huehueteotl

September 10, 2007 at 9:11 am

Posted in HIV, Psychology, what I read

How Antibodies Fight HIV: New Evidence

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By furthering scientists’ understanding of the molecular mechanisms that separate the minority of successful HIV antibodies from the majority of ineffective antibodies, the work may have implications for future attempts to design an HIV vaccine. The study was published on September 6, 2007, in the journal Nature,

“This study is part of the effort to understand how protection against HIV occurs,” says Dennis Burton, a professor at The Scripps Research Institute. “If we really understand this, then we can design tailor-made vaccines in a way that has never been done before.”

Although vaccines have long been used with great success to prevent diseases, scientists are still learning about the exact mechanisms of how vaccines work and how the antibodies that vaccines prompt the body to create can neutralize a pathogen. The spread of HIV, which is resistant to most antibodies the body produces against it, has made fully understanding this method of action more urgent.

With this in mind, Burton and colleagues sought to tease apart the action of the b12 antibody-one of the rare antibodies that protects against the HIV virus. The antibody, first identified by Burton, Scripps Research Professor Carlos Barbas III, and colleagues in 1992, originally came from the bone marrow of a 31-year-old male who had been HIV positive without symptoms for six years.

In the current study, researchers created mutated versions of b12 to see what effect various changes would have on the antibody’s effectiveness.

“Hopefully, we can work backwards towards a vaccine, using b12 and the very few other really great, broadly neutralizing antibodies against HIV that have been found,” says Scripps Research Senior Research Associate Ann Hessell, who was first author of the Nature paper jointly with Lars Hangartner, a Scripps Research postdoctoral fellow.

Results from the new study suggest the importance of antibody activity against both infected cells and free virus for effective protection. As well as simply binding to HIV, protection was dependent upon the ability of antibodies to interact with immune cell Fc receptors.

Fc receptors are found on the surface of immune cells, such as natural killer cells. The Fc receptor binds to the Fc region of an antibody after an antibody binds to a pathogen, targeting the pathogen for attack by the immune system. Although Fc receptor function was known to be important for the function of antibodies against other diseases, a role in protecting against HIV had never before been demonstrated.

Burton’s team examined the ability of two antibodies mutated from b12, dubbed KA and LALA, to prevent infection using the SHIV/macaque model, in which macaques are challenged with a hybrid human-simian virus that infects the model but is recognized by human antibodies. The KA antibody contained a mutation that prevented it from interacting with the complement cascade, a major component of the immune system responsible for destroying invading pathogens. The LALA antibody contained a mutation that rendered it unable to interact with either the complement pathway or the Fc receptor.

In both mutants, the site where the antibody binds to free-floating virus was unaltered, allowing the researchers specifically to investigate the importance of the complement cascade and Fc receptor system for preventing infection.

“We saw that the KA antibody, which could still bind to the Fc receptors on the immune cells but not to the complement cascade, protected the animals from becoming infected just as the wild type b12 antibody,” says Hessell. “In contrast, the LALA group became infected much like the controls.”

The results provide the first evidence that the Fc receptor, but not the complement cascade, is important to the function of the b12 antibody in preventing HIV infection.

Additional in vitro experiments revealed that the wild type and KA antibodies, but not the LALA antibody, blocked infection more efficiently in the presence of other effector cells of the immune system.

“Our results are fully consistent with the antibody doing two jobs,” says Burton, “job one, stick to the virus; job two, recruit immune cells to come and kill infected cells.”

Nature. 2007 Sep 6;449(7158):101-4.

Fc receptor but not complement binding is important in antibody protection against HIV.

Hessell AJ, Hangartner L, Hunter M, Havenith CE, Beurskens FJ, Bakker JM, Lanigan CM, Landucci G, Forthal DN, Parren PW, Marx PA, Burton DR.

Department of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.

see also:

J Immunol. 2007 Sep 1;179(5):3144-52.

Inhibition of HIV-1 Infectivity and Epithelial Cell Transfer by Human Monoclonal IgG and IgA Antibodies Carrying the b12 V Region.

Mantis NJ, Palaia J, Hessell AJ, Mehta S, Zhu Z, Corthésy B, Neutra MR, Burton DR, Janoff EN.

Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY 12208.

Both IgG and secretory IgA Abs in mucosal secretions have been implicated in blocking the earliest events in HIV-1 transit across epithelial barriers, although the mechanisms by which this occurs remain largely unknown. In this study, we report the production and characterization of a human rIgA(2) mAb that carries the V regions of IgG1 b12, a potent and broadly neutralizing anti-gp120 Ab which has been shown to protect macaques against vaginal simian/HIV challenge. Monomeric, dimeric, polymeric, and secretory IgA(2) derivatives of b12 reacted with gp120 and neutralized CCR5- and CXCR4-tropic strains of HIV-1 in vitro. With respect to the protective effects of these Abs at mucosal surfaces, we demonstrated that IgG1 b12 and IgA(2) b12 inhibited the transfer of cell-free HIV-1 from ME-180 cells, a human cervical epithelial cell line, as well as Caco-2 cells, a human colonic epithelial cell line, to human PBMCs. Inhibition of viral transfer was due to the ability of b12 to block both viral attachment to and uptake by epithelial cells. These data demonstrate that IgG and IgA MAbs directed against a highly conserved epitope on gp120 can interfere with the earliest steps in HIV-1 transmission across mucosal surfaces, and reveal a possible mechanism by which b12 protects the vaginal mucosal against viral challenge in vivo.

Written by huehueteotl

September 7, 2007 at 11:29 am

Posted in HIV, what I read