HIV testing among pregnant women living with HIV in India: are private healthcare providers routinely violating women's human rights?

BACKGROUND: In India, approximately 49,000 women living with HIV become pregnant and deliver each year. While the government of India has made progress increasing the availability of prevention of mother-to-child transmission of HIV (PMTCT) services, only about one quarter of pregnant women received an HIV test in 2010, and about one-in-five that were found positive for HIV received interventions to prevent vertical transmission of HIV. METHODS: Between February 2012 to March 2013, 14 HIV-positive women who had recently delivered a baby were recruited from HIV positive women support groups, Government of India Integrated Counseling and Testing Centers, and nongovernmental organizations in Mysore and Pune, India. In-depth interviews were conducted to examine their general experiences with antenatal healthcare; specific experiences around HIV counseling and testing; and perceptions about their care and follow-up treatment. Data were analyzed thematically using the human rights framework for HIV testing adopted by the United Nations and India's National AIDS Control Organization. RESULTS: While all of the HIV-positive women in the study received HIV and PMTCT services at a government hospital or antiretroviral therapy center, almost all reported attending a private clinic or hospital at some point in their pregnancy. According to the participants, HIV testing often occurred without consent; there was little privacy; breaches of confidentiality were commonplace; and denial of medical treatment occurred routinely. Among women living with HIV in this study, violations of their human rights occurred more commonly in private rather than public healthcare settings. CONCLUSIONS: There is an urgent need for capacity building among private healthcare providers to improve standards of practice with regard to informed consent process, HIV testing, patient confidentiality, treatment, and referral of pregnant women living with HIV.

Building research ethics capacity in post-communist countries: experience of two Fogarty training programs.

The post-Communist countries of Central and Eastern Europe and Central Asia are at various stages of development with respect to their capacity to protect human research participants. We examined the impact of two Fogarty-funded programs in this region, the Union Graduate College-Vilnius University Advanced Certificate Program and the Case Western Reserve University Master's Degree Program, by surveying these programs' graduates and by examining alumni activities. Alumni have served in leadership roles on research ethics committees, developed and taught new courses in research ethics, and contributed to scholarship. However, political, social, and economic challenges impede the ability of graduates to maximize their effectiveness. Additional curricular attention is needed in research methodology, policy development and implementation, and the interplay between research ethics and human rights.

An analysis of online courses in research ethics in the Fogarty-sponsored bioethics training programs.

Several training programs sponsored by the NIH/Fogarty International Center's International Research Ethics Education and Curriculum Development Program offer online graduate-level courses in research ethics to participants in lowand middle-income countries. This paper describes the evaluation of four of these online courses and recommendations for improvements to achieve the highest-quality design and delivery. We used an evaluation matrix consisting of 95 criteria based on recommended best practices in eLearning. Our results showed that these courses are developing or meeting nearly 73% of the criteria, while they are not meeting approximately 21% of the criteria. Together, one or more of the courses are developing or meeting 89 of the 95 criteria. These results suggest that the necessary skills and expertise exist in these programs to bring all of the eLearning courses close to 100% proficiency by sharing a common set of best practices. This paper is part of a collection of articles analyzing the Fogarty International Center's International Research Ethics Education and Curriculum Development Program.

Natural Scrub Typhus Antibody Suppresses HIV CXCR4(X4) Viruses.

Viral load generally rises in HIV-infected individuals with a concomitant infection, but falls markedly in some individuals with scrub typhus (ST), a common Asian rickettsial infection. ST infection appears to shift the viral population from CXCR4-using (X4) to CCR5-utilizing (R5) strains, and there is evidence of cross-reactivity between ST-specific antibodies and HIV-1. We examined the mechanism of ST suppression of HIV by measuring the effects of ST infection on X4 and R5 viruses in vivo and in vitro, and assessing the relative contributions of antibodies and chemokines to the inhibitory effect. In vivo, a single scrub typhus plasma infusion markedly reduced the subpopulation of HIV-1 viruses using the X4 co-receptor in all 8 recipients, and eliminated X4 viruses 6 patients. In vitro, the 14 ST sera tested all inhibited the replication of an X4 but not an R5 virus. This inhibitory effect was maintained if ST sera were depleted of chemokines but was lost upon removal of antibodies. Sera from STinfected mice recognized a target that co-localized with X4 HIV gp120 in immunofluorescent experiments. These in vivo and in vitro data suggest that acute ST infection generates cross-reactive antibodies that produce potent suppression of CXCR4- but not CCR5-using HIV-1 viruses. ST suppression of HIV replication could reveal novel mechanisms that could be exploited for vaccination strategies, as well as aid in the development of fusion inhibitors and other new therapeutic regimens. This also appears to be the first instance where one pathogen is neutralized by antibody produced in response to infection by a completely unrelated organism.

Protecting participants of clinical trials conducted in the intensive care unit.

Research in the intensive care unit (ICU) raises a number of scientific and ethical challenges. Potential participants in critical care studies are likely to be considered particularly vulnerable-they may lack sufficient capacity to make informed decisions about trial participation, their health care proxies may lack legal authority to enroll them in research trials or may not know their true intent, and the life-threatening nature of the illness may make them or their surrogates more susceptible to therapeutic misconception. Because of this, critical care investigators must exercise extreme caution when designing and conducting studies in the ICU. In this article, we review the key literature addressing the various scientific and ethical issues raised by critical care research, including questions of equipoise and the selection of control groups, informed consent, therapeutic misconception, conflict of interest, and quality improvement projects. We also describe the current status of key policy or regulatory initiatives designed to address these issues, particularly in light of recent controversies involving critical care studies like the ARDSNet trial.

The challenge of defining standards of prevention in HIV prevention trials.

As new HIV prevention tools are developed, researchers face a number of ethical and logistic questions about how and when to include novel HIV prevention strategies and tools in the standard prevention package of ongoing and future HIV prevention trials. Current Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO) guidance recommends that participants in prevention trials receive 'access to all state of the art HIV risk reduction methods', and that decisions about adding new tools to the prevention package be made in consultation with 'all relevant stakeholders'. The guidance, however, leaves open questions of both process and implementation. In March 2009, the Global Campaign for Microbicides, UNAIDS and the Centers for Disease Control and Prevention convened a consultation to develop practical answers to these questions. Fifty-nine diverse participants, including researchers, ethicists, advocates and policymakers, worked to develop consensus criteria on when to include new HIV prevention tools in future trials. Participants developed a set of questions to guide decision-making, including: whether the method has been recommended by international bodies or adopted at a national level; the size of the effect and weight of the evidence; relevance to the trial population; whether the tool has been approved or introduced in the trial country; whether adding the tool might lead to trial futility; outstanding safety issues and status of the trial. Further work is needed to develop, implement and evaluate approaches to facilitate meaningful stakeholder participation in this deliberative process.

Transition from long-term nonprogression to HIV-1 disease associated with escape from cellular immune control.

Transition from long-term nonprogressive infection to progressive HIV-1 disease presents an opportunity to investigate pathogenesis in a defined immunogenetic background. We studied a male long-term nonprogressor (LTNP) who remained asymptomatic and viremic and had normal CD4 T-cell counts without antiretroviral therapy for >18 years and then experienced a transition to disease progression. We analyzed the complete HIV-1 genomic RNA sequence from plasma and cellular immune responses to predefined human leukocyte antigen-matched autologous viral peptides spanning the viral genome, before and after progression. Serial viral sequences did not seem attenuated and consistently utilized coreceptor CCR5. LTNP status was associated with elongated V2 domains and broad low-level T-cell immune responses targeting several regions of the viral genome. The transition to progressive disease was associated with the acquisition of viral mutations conferring escape from CD8 T-cell responses. Multiple changes in HIV-1 sequence and loss of immune response over time most likely contributed to the transition from LTNP status to progressive disease. These data are relevant to vaccine design and identification of the correlates of protection from disease progression.

HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy.

BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/microl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

The convergence of research and clinical practice: institutional review board review of humanitarian use device applications.

WE SURVEYED IRB CHAIRS IN THE United States to ascertain whether their IRBs have clarity regarding their FDA-mandated role in reviewing humanitarian use device (HUD) applications, which are neither research devices nor fully tested treatments. Of 2,588 Chairs, 469 (18%) completed the survey, almost half of whom (44%) reported review of a HUD application within the previous five years. Findings suggest that many IRB Chairs are confused about what HUDs are, how to review HUD applications, and why IRBs should review them. We recommend that the FDA clarify their policies so that Chairs can provide the guidance necessary for IRBs to more effectively and consistently review HUD applications, and thereby better protect HUD-treated patients.

Structural basis for coreceptor selectivity by the HIV type 1 V3 loop.

The third variable region (V3) of the HIV-1 surface glycoprotein, gp120, plays a central role in the interaction of the virus envelope with the cell surface chemokine receptors, triggering membrane fusion and virus entry into human lymphocytes and macrophages. The CXCR4 and CCR5 chemokine receptors are used by "X4-tropic" and "R5-tropic" viruses, respectively. Recently, the crown of the V3 loop was shown to bear a close structural homology to the beta2-beta3 loop in the CXC and CC chemokines, the natural ligands of CXCR4 and CCR5, respectively. This homology can serve as the foundation for 3D molecular modeling of the V3 loops from primary isolates whose coreceptor usage was experimentally defined. The modeling revealed a charged "patch" on the surface of V3 that correlates with coreceptor usage. This V3 surface patch is positively charged in X4-tropic viruses and negatively charged or neutral in R5-tropic viruses, and is formed by two amino acids, at position 11 and at position 24 or 25; amino acids 11 and 24 or 11 and 25 contact each other in 3D space. Residues at positions 11 and 25 were known previously to influence coreceptor usage, and the charge of the residues at these two positions is often used to predict viral tropism. However, we found that the predictive value of using the charge of residues 11, 24, and 25 to identify X4 or R5 tropism was improved over using only the charge of residues 11 and 25. Thus, the data suggest a new " 11/24/25 rule" : a positively charged amino acid at position 11, 24, or 25 defines X4; otherwise R5. This rule gave an overall predictive value of 94% for 217 viruses whose tropism had been determined experimentally as either X4 or R5. The results have additional implications for the design of HIV therapeutics, vaccines, and strategies for monitoring disease progression.

Federalism & bioethics: states and moral pluralism.

Bioethicists are often interested mostly in national standards and institutions, but state governments have historically overseen a wide range of bioethical issues and share responsibility with the federal government for still others. States ought to have an important role. By allowing for multiple outcomes, the American federal system allows a better fit between public opinion and public policies.

Validity and utility of a LRRK2 G2019S mutation test for the diagnosis of Parkinson's disease.

The G2019S mutation in the LRRK2 gene, the most common known cause of Parkinson's disease (PD), will soon be widely available as a molecular clinical test for PD. The objective of this study was to assess performance characteristics of G2019S as a clinical test for PD in the setting of typical movement disorder clinics in the United States. Subjects included 1,518 sequentially recruited PD patients from seven movement disorder clinics in the United States, and 1,733 unaffected subjects. All 3,251 subjects were genotyped for the G2019S mutation using a TaqMan assay, and mutations were verified by direct sequencing. Test validity estimates were calculated using standard methods. A total of 20/1518 patients and 1/1733 controls carried the G2019S mutation. Specificity was 99.9% (95% CI, 99.6-100%), sensitivity was 1.3% (0.8-2.1%), and the positive likelihood ratio was 22.8. A positive family history of PD increased the positive likelihood ratio to 82.5. Information on gender, age at disease onset, or age at testing did not improve test performance. The gene test was highly accurate in classifying mutation carriers as PD, but it performed poorly in predicting the phenotype of non-mutation carriers. A G2019S molecular test for PD would be highly specific, technically simple, and inexpensive. Test interpretation is straightforward when used for diagnosis of symptomatic individuals, but is more complex for risk assessment and predictive testing in asymptomatic individuals. Test results can have psychological, social, and economical ramifications; thus, proper counseling is essential.

Prevalence of drug-resistance mutations and non-subtype B strains among HIV-infected infants from New York State.

Prevalence studies indicate that transmission of drug-resistant HIV has been rising in the adult population, but data from the perinatally infected pediatric population are limited. In this retrospective study, we sequenced the pol region of HIV from perinatally infected infants diagnosed in New York State in 2001-2002. Analyses of drug resistance, subtype diversity, and perinatal antiretroviral exposure were conducted, and the results were compared with those from a previous study of HIV-infected infants identified in 1998-1999. Eight of 42 infants (19.1%) had provirus carrying at least 1 drug-resistance mutation, an increase of 58% over the 1998-1999 results. Mutations conferring resistance to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors were detected in 7.1%, 11.9%, and 2.4% of specimens, respectively. Consistent with previous results, perinatal antiretroviral exposure was not associated with drug resistance (P = 0.70). Phylogenetic analysis indicated that 16.7% of infants were infected with a non-subtype B strain of HIV. It seems that drug-resistant and non-subtype B strains of HIV are becoming increasingly common in the perinatally infected population. Our results highlight the value of resistance testing for all HIV-infected infants upon diagnosis and the need to consider subtype diversity in diagnostic and treatment strategies.