scholarly journals Is it ethical to isolate study participants to prevent HIV transmission during trials with an analytical treatment interruption?

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S19-S21
Author(s):  
Nir Eyal ◽  
Monica Magalhaes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Transmission ◽  
Treatment Interruption ◽  
Sex Partners ◽  
Analytical Treatment ◽  
Immunodeficiency Virus ◽  
Study Participants

Abstract This commentary considers an extreme idea for protecting against human immunodeficiency virus (HIV) transmission to sex partners of individuals participating in HIV remission studies with an analytical treatment interruption (ATI). Other human challenge studies, such as studies of influenza, commonly isolate participants during the trial, to protect their contacts and the community against infection. Why should HIV studies with a treatment interruption be any different, one might wonder? This article concludes that isolation should not be used in HIV remission studies with an ATI but also shows that the matter is complex.

scholarly journals Preexposure Prophylaxis for Mitigating Risk of HIV Transmission During HIV Cure–Related Clinical Trials With a Treatment Interruption

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S16-S18 ◽  
Author(s):  
Jean-Daniel Lelièvre
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Hiv Transmission ◽  
Treatment Interruption ◽  
Sex Partners ◽  
Hiv Cure ◽  
Analytical Treatment ◽  
Secondary Transmission ◽  
Preexposure Prophylaxis ◽  
Immunodeficiency Virus

AbstractAnalytical treatment interruption performed during human immunodeficiency virus (HIV) cure–related clinical trials exposes sex partners of participants in these trials to a risk of HIV transmission. Preexposure prophylaxis (PrEP), which emerged in recent years as a key strategy for preventing HIV transmission, is often considered a useful tool to prevent this risk. This article supports offering PrEP to the stable sex partners of participants in these trials but also notes limitations that must be addressed. It concludes that PrEP cannot on its own eliminate the risk of secondary transmission in this context.

scholarly journals Human Immunodeficiency Virus Transmission Risk in Analytical Treatment Interruption Studies: Relational Factors and Moral Responsibility

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S12-S15 ◽  
Author(s):  
Liza Dawson
Keyword(s):  
Human Immunodeficiency Virus ◽  
Risk Mitigation ◽  
Healthcare Providers ◽  
Virus Transmission ◽  
Treatment Interruption ◽  
Mitigation Strategies ◽  
Transmission Risk ◽  
Analytical Treatment ◽  
Immunodeficiency Virus ◽  
Study Participants

Abstract Analytical treatment interruption (ATI) is becoming common in human immunodeficiency virus (HIV) cure-related research, but its use is controversial. ATI raises concerns about risks of HIV transmission to sexual partners of study participants. Researchers may have difficulty addressing these risks, given that study participants’ private behavior is implicated, the partners are not enrolled in the research, and behavioral HIV risk mitigation strategies usually fall outside the study objectives. This analysis argues that researchers should assume some responsibility for partners’ risks, based on the importance of partner relationships for the study participants themselves, and out of concern for the partners’ welfare. Adding this responsibility is reasonable since the risk is created in part by research procedures, and since concern for third parties is often part of professional standards for healthcare providers. Study participants and their partners also bear some responsibility. Specific recommendations for measures to address risk are discussed.

scholarly journals Impact of Treatment Interruption on HIV Reservoirs and Lymphocyte Subsets in Individuals Who Initiated Antiretroviral Therapy During the Early Phase of Infection

2019 ◽  
Vol 220 (2) ◽  
pp. 270-274 ◽  
Author(s):  
Erin D Huiting ◽  
Kathleen Gittens ◽  
J Shawn Justement ◽  
Victoria Shi ◽  
Jana Blazkova ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Early Phase ◽  
Lymphocyte Subsets ◽  
Treatment Interruption ◽  
Therapeutic Strategies ◽  
Clinical Protocols ◽  
Analytical Treatment ◽  
Hiv Reservoirs ◽  
Immunodeficiency Virus

Abstract Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)–infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.

scholarly journals Risk to Nonparticipants in HIV Remission Studies With Treatment Interruption: A Symposium

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S1-S4 ◽  
Author(s):  
Nir Eyal ◽  
Steven G Deeks
Keyword(s):  
Human Subjects ◽  
Treatment Interruption ◽  
Sex Partners ◽  
Hiv Cure ◽  
Ethical Guidelines ◽  
Treatment Interruptions ◽  
Immunodeficiency Virus ◽  
Practical Challenge ◽  
Guidelines And Recommendations ◽  
Study Participants

AbstractEthical guidelines and recommendations for human subjects research typically focus on protecting the individuals who directly participate in that research. However, additional people, including sex partners of research participants, can also face harms and burdens from medical studies. In human immunodeficiency virus (HIV) cure–related research, a persistent ethical and practical challenge surrounds the use of analytical antiretroviral treatment interruptions. The challenge is usually discussed in relation to risks to study participants, but serious dangers accrue to nonparticipants, including sex partners of study participants. This multidisciplinary supplement relays the risks for nonparticipating sex partners in HIV cure–related studies and addresses the ethical dilemmas raised by these studies, with recommendations for researchers, advocates, sponsors, and oversight bodies.

scholarly journals Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Ria Goswami ◽  
Ashley N. Nelson ◽  
Joshua J. Tu ◽  
Maria Dennis ◽  
Liqi Feng ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Short Term ◽  
Analytical Treatment ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Immunodeficiency Virus

ABSTRACT To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure. IMPORTANCE Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.

scholarly journals Removing One Barrier to Protecting Sex Partners in HIV Remission Studies With a Treatment Interruption

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S22-S23
Author(s):  
Nir Eyal
Keyword(s):  
Treatment Interruption ◽  
Sexual Partners ◽  
Sex Partners ◽  
Analytical Treatment ◽  
Study Participants ◽  
Made In

Abstract Only a few of the recommendations made in this supplement are implemented in ongoing HIV remission studies that involve an analytical treatment interruption. The absence of these recommendations in protocols puts sexual partners of study participants at serious risk. This paper addresses one possible barrier to implementation: a certain misunderstanding among sponsors and research entities.

scholarly journals Novel Strategy To Adapt Simian-Human Immunodeficiency Virus E1 Carryingenvfrom an RV144 Volunteer to Rhesus Macaques: Coreceptor Switch and Final Recovery of a Pathogenic Virus with Exclusive R5 Tropism

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
Hanna B. Scinto ◽  
Sandeep Gupta ◽  
Swati Thorat ◽  
Muhammad M. Mukhtar ◽  
Anthony Griffiths ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Placebo Recipient ◽  
T Cell ◽  
Hiv Transmission ◽  
Rhesus Macaques ◽  
Phase Iii ◽  
Immunodeficiency Virus ◽  
Coreceptor Switch ◽  
Novel Strategy ◽  
Hiv Acquisition

ABSTRACTThe phase III RV144 human immunodeficiency virus (HIV) vaccine trial conducted in Thailand remains the only study to show efficacy in decreasing the HIV acquisition risk. In Thailand, circulating recombinant forms of HIV clade A/E (CRF01_AE) predominate; in such viruses,envoriginates from clade E (HIV-E). We constructed a simian-human immunodeficiency virus (SHIV) chimera carryingenvisolated from an RV144 placebo recipient in the SHIV-1157ipd3N4 backbone. The latter contains long terminal repeats (LTRs) with duplicated NF-κB sites, thus resembling HIV LTRs. We devised a novel strategy to adapt the parental infectious molecular clone (IMC), R5 SHIV-E1, to rhesus macaques: the simultaneous depletion of B and CD8+cells followed by the intramuscular inoculation of proviral DNA and repeated administrations of cell-free virus. High-level viremia and CD4+T-cell depletion ensued. Passage 3 virus unexpectedly caused acute, irreversible CD4+T-cell loss; the partially adapted SHIV had become dual tropic. Virus and IMCs with exclusive R5 tropism were reisolated from earlier passages, combined, and used to complete adaptation through additional macaques. The final isolate, SHIV-E1p5, remained solely R5 tropic. It had a tier 2 neutralization phenotype, was mucosally transmissible, and was pathogenic. Deep sequencing revealed 99% Env amino acid sequence conservation; X4-only and dual-tropic strains had evolved independently from an early branch of parental SHIV-E1. To conclude, our primate model data reveal that SHIV-E1p5 recapitulates important aspects of HIV transmission and pathobiology in humans.IMPORTANCEUnderstanding the protective principles that lead to a safe, effective vaccine against HIV in nonhuman primate (NHP) models requires test viruses that allow the evaluation of anti-HIV envelope responses. Reduced HIV acquisition risk in RV144 has been linked to nonneutralizing IgG antibodies with a range of effector activities. Definitive experiments to decipher the mechanisms of the partial protection observed in RV144 require passive-immunization studies in NHPs with a relevant test virus. We have generated such a virus by insertingenvfrom an RV144 placebo recipient into a SHIV backbone with HIV-like LTRs. The final SHIV-E1p5 isolate, grown in rhesus monkey peripheral blood mononuclear cells, was mucosally transmissible and pathogenic. Earlier SHIV-E passages showed a coreceptor switch, again mimicking HIV biology in humans. Thus, our series of SHIV-E strains mirrors HIV transmission and disease progression in humans. SHIV-E1p5 represents a biologically relevant tool to assess prevention strategies.

scholarly journals DC-SIGN Interactions with Human Immunodeficiency Virus: Virus Binding and Transfer Are Dissociable Functions

2001 ◽  
Vol 75 (21) ◽  
pp. 10523-10526 ◽  
Author(s):  
Stefan Pöhlmann ◽  
George J. Leslie ◽  
Terri G. Edwards ◽  
Todd Macfarlan ◽  
Jacqueline D. Reeves ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Surface ◽  
Hiv Transmission ◽  
Virus Transmission ◽  
Underlying Mechanism ◽  
Virus Binding ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Virus

ABSTRACT The C-type lectins DC-SIGN and DC-SIGNR capture and transfer human immunodeficiency virus (HIV) to susceptible cells, although the underlying mechanism is unclear. Here we show that DC-SIGN/DC-SIGNR-mediated HIV transmission involves dissociable binding and transfer steps, indicating that efficient virus transmission is not simply due to tethering of virus to the cell surface.

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