Lifelong Antiretroviral Therapy Research Articles

Sequence Analysis of Inducible, Replication-Competent Virus Reveals No Evidence of HIV-1 Evolution During Suppressive Antiviral Therapy, Indicating a Lack of Ongoing Viral Replication.

Persistence of HIV-1 in reservoirs necessitates life-long antiretroviral therapy (ART). There are conflicting data using genetic analysis on whether persistence includes an actively replicating reservoir with strong evidence arguing against replication. We investigated the possibility of ongoing viral evolution during suppressive therapy by comparing near full-length viral genomic sequences using phylogenetic analysis of viral RNA in plasma before therapy initiation early after infection and from virus induced to grow from the latent reservoir after a period of suppressive ART. We also focused our analysis on evidence of selective pressure by drugs in the treatment regimen and at sites of selective pressure by the adaptive immune response. Viral genomes induced to grow from the latent reservoir from 10 participants with up to 9 years on suppressive ART were highly similar to the nearly homogeneous sequences in plasma taken early after infection at ART initiation. This finding was consistent across the entire genome and when the analysis focused on sites targeted by the drug regimen and by host selective pressure of antibody and cytotoxic T cells. The lack of viral evolution away from pretherapy sequences in spite of demonstrated selective pressure is most consistent with a lack of viral replication during reservoir persistence. These results do not support ongoing viral replication as a mechanism of HIV-1 persistence during suppressive ART.

Adherence of denosumab treatment for low bone mineral density in Japanese people living with HIV: a retrospective observational study

BackgroundLong-term care issues, specifically metabolic bone disorders, are a concern for people living with human immunodeficiency virus (PLWH) who undergo life-long antiretroviral therapy (ART). Previous clinical trials with denosumab, an anti-RANKL antibody inhibitor, have revealed its effectiveness in increasing bone mineral density (BMD) in patients with osteoporosis. However, there are limited data on adherence and effectiveness of denosumab treatment for osteoporosis in PLWH. Hence, this study aimed to investigate the adherence and effectiveness of denosumab treatment for osteoporosis in Japanese PLWH.MethodsThis study is a retrospective exploratory analysis of 29 Japanese PLWH who initiated denosumab treatment for osteoporosis, between 2013 and 2021. The study included patients who received at least one dose of denosumab every 6 months. Adherence and persistence were defined as receiving two consecutive injections of denosumab 6 months ± 4 weeks apart and 6 months + 8 weeks apart, respectively. The primary outcome measure of the study was the adherence of denosumab treatment for 24 months. The secondary outcome measures included treatment persistence and BMD. The period after January 2020 was defined as the coronavirus disease 2019 (COVID-19) pandemic period, and its impact on adherence was investigated.ResultsThe treatment adherence rates at 12 and 24 months were 89.7% and 60.7%, respectively. By contrast, the treatment persistence at 12 and 24 months was 100% and 85.7%, respectively. More patients in the group who initiated denosumab treatment after the COVID-19 pandemic reached non-adherence than in the group who initiated denosumab treatment before the pandemic. BMD at the lumbar spine and femoral neck significantly increased compared to that at baseline, with median percentage changes of 8.7% (p < 0.001) and 3.5% (p = 0.001), respectively.ConclusionsThe results showed that patients in the study had a high rate of non-adherence but a lower rate of non-persistence. Additionally, PLWH on ongoing ART experienced increased BMD with denosumab treatment. This study provides an opportunity to improve future strategies for denosumab treatment in the Japanese PLWH.

Womandla Health: development and rationale of a behavioral intervention to support HIV treatment adherence among postpartum women in South Africa

BackgroundWhile Option B + has made great strides in eliminating vertical transmission of HIV and improving access to lifelong antiretroviral therapy (ART) for women, the postpartum period remains a risk period for disengagement from HIV care and non-adherence.MethodsLongitudinal qualitative data was collected from 30 women living with HIV in Cape Town, South Africa from pregnancy through 1 year postpartum to examine key barriers and facilitators to HIV treatment adherence across this transition. Participants were also asked about their preferences for behavioral intervention content, format, and scope. The intervention development process was guided by Fernandez et al.’s Intervention Mapping process and was informed by the qualitative data, the wider literature on ART adherence, and Transition Theory.ResultsThe Womandla Health Intervention is a multicomponent intervention consisting of four individual sessions with a lay health worker and four peer group sessions, which span late pregnancy and early postpartum. These sessions are guided by Transition Theory and utilize motivational interviewing techniques to empower women to ascertain their own individual barriers to HIV care and identify solutions and strategies to overcome these barriers.ConclusionsThis intervention will be tested in a small scale RCT. If successful, findings will provide an innovative approach to HIV treatment by capitalizing on the transition into motherhood to bolster self-care behaviors, focusing on ART adherence and also women’s overall postpartum health and psychosocial needs.

HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study

Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission. IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks' gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m2 and lopinavir 300 mg/m2 from 14 days of life and 42 weeks postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption. This study is registered with ClinicalTrials.gov, NCT02140255. Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17-49) in cohort 1 and 57% (28-78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31-89) in cohort 1 and five of seven (71%, 29-96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52-100) in cohort 1 and all seven (100%, 59-100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2. Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission. National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Immunogenic arenavirus vector SIV vaccine reduces setpoint viral load in SIV-challenged rhesus monkeys

HIV affects more than 38 million people worldwide. Although HIV can be effectively treated by lifelong combination antiretroviral therapy, only a handful of patients have been cured. Therapeutic vaccines that induce robust de novo immune responses targeting HIV proteins and latent reservoirs will likely be integral for functional HIV cure. Our study shows that immunization of naïve rhesus macaques with arenavirus-derived vaccine vectors encoding simian immunodeficiency virus (SIVSME543 Gag, Env, and Pol) immunogens is safe, immunogenic, and efficacious. Immunization induced robust SIV-specific CD8+ and CD4+ T-cell responses with expanded cellular breadth, polyfunctionality, and Env-binding antibodies with antibody-dependent cellular cytotoxicity. Vaccinated animals had significant reductions in median SIV viral load (1.45-log10 copies/mL) after SIVMAC251 challenge compared with placebo. Peak viral control correlated with the breadth of Gag-specific T cells and tier 1 neutralizing antibodies. These results support clinical investigation of arenavirus-based vectors as a central component of therapeutic vaccination for HIV cure.

Prior exposure to antiretroviral therapy among adult patients presenting for HIV treatment initiation or reinitiation in sub-Saharan Africa: a systematic review

ObjectivesAs countries have scaled up access to antiretroviral therapy (ART) for HIV, attrition rates of up to 30% annually have created a large pool of individuals who initiate treatment with...

Preferences for enhanced treatment options to address HIV care engagement among women living with HIV and perinatal depression in Malawi

BackgroundOption B + offers lifelong ART to pregnant or breastfeeding mothers, but postpartum loss to HIV care, partially driven by perinatal depression (PND), threatens the impact of this policy. This study aims to understand women’s and providers’ preferences for developing a feasible intervention to address PND and support engagement in HIV care among women living with PND and HIV.MethodsWe conducted a total of 6 focus group discussions (FGDs) involving 4 clinics in Lilongwe District from December 2018 through February 2019. We conducted 2 FGDs each among 3 stakeholder groups: clinical staff, prenatal women, and postnatal women. Perinatal participants were living with HIV and screened positively for PND using the validated Edinburgh Postnatal Depression Scale (EPDS). Clinical staff were nurses who were trained antiretroviral therapy (ART) providers. Interviewers led FGDs in Chichewa using a semi-structured guide. Data were analyzed using deductive and inductive coding in NVivo 12 software.ResultsWomen favored ART linkage services, but providers said they already offered such services, with mixed results. Individual counselling was universally supported. A perceived benefit of group counselling was peer support, but there were concerns among women regarding confidentiality and stigma. Women liked mobile appointment reminders but identified low phone ownership as a barrier. Participants recommended home visits as an additional care engagement strategy. Women consistently discussed the need for social support from family members and friends to address PND and support engagement in HIV care.ConclusionThis study highlights the importance of peer encouragement to support perinatal HIV care engagement among women with HIV and PND. The results from this study can be used to support intervention development to increase HIV care engagement and improve long-term HIV outcomes in women with PND.

The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy.

HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART.

Overview of Knowledge of Pregnant Women About the Dangers of HIV/AIDS at the Pratama Nusantara Clinic Mandau District Bengkalis Regency in 2019

HIV/AIDS is a relatively well-known disease with many health problems, especially when it occurs in pregnant women. Dangers that can occur such as immune system disorders and pregnant women are susceptible to infection, pregnancy will fight the progress of HIV infection, conversely the effects of HIV in pregnancy are intra uterine growth retardation and low birth weight, as well as increased preterm birth and the baby can also be infected in the womb. HIV continues to be a major problem in the world, so far it has claimed more than 35 million lives. At the end of 2017, there were around 36.5 million people living with HIV and 1.8 million people newly infected with HIV worldwide. About 59% of adults and 52% of children with HIV are on lifelong antiretroviral therapy (ART). The high coverage of ART in the world for pregnant and lactating women is 80%. This study aims to describe the knowledge of pregnant women about the dangers of HIV/AIDS at the Pratama Nusantara Clinic, Mandau District, Bengkalis Regency in 2019. The research design used is descriptive quantitative. The research was conducted from June 1 to June 20 2019. The population in this study consisted of 38 pregnant women with a sample of 35 people using Simple Random Sampling. Data were obtained from primary and secondary data for further analysis of the data univariately. The results showed that the majority of pregnant women lacked knowledge about the dangers of HIV/AIDS as many as 18 people (51.43%), at the age of 20-35 years as many as 10 people (28.57%), high school education level as many as 8 people (22.86 %) %), and 7 people (20%) got information about the dangers of HIV/AIDS through electronic media. It is expected that pregnant women will further increase their knowledge by adding information from various media and more often participate in counseling programs conducted by health workers/facilities and participate in carrying out HIV/AIDS testing during pregnancy.

Trends Analysis of HIV Infection and Antiretroviral Treatment Outcome in Amhara Regional from 2015 to 2021, Northeast Ethiopia.

The persistent efforts of HIV/AIDS epidemiology remain one of the world's most important community health threats. To avoid becoming an epidemic, UNAIDS has set three 90% fast-track targets for 2020, and Ethiopia has also changed its implementation since 2015. However, the achievement targets in the Amhara region have yet to be evaluated at the end of the programme period. The aim of this study was to assess the Trends of HIV Infection and Antiretroviral Treatment outcome in Eastern Amhara Regional from 2015 to 2021, Northeast Ethiopia. A retrospective study was conducted by reviewing the District Health Information System from 2015 to 2021. The collected data includes the trend of HIV testing services, the trend of HIV positivity, the yield of HIV testing approaches, the number of HIV positive patients linked to HIV care and treatment or access to lifelong antiretroviral therapy, viral load testing coverage, and viral suppression. A descriptive statistic and trend analysis were computed. A total of 145,639 people accessed antiretroviral therapy. The trend of HIV test positivity has been declining since 2015, peaking at 0.76% in 2015 and declining to 0.60% in 2020. A high level of positivity was reported in volunteer counselling and testing as compared with provider-initiated testing and counselling services. Following an HIV positive, there was an increase in linkage to HIV care and treatment. High suppression rates of viral load indicate testing coverage grew over time. The viral load monitoring coverage was 70% in 2021, with a viral suppression rate of 94%. The trend in achievement in the first 90s was not consistent with predefined goals (90%). On the other hand, there was good achievement in the second and third goals. Hence, intensified case-finding approaches to HIV testing should be strengthened.

Retesting of Patients Receiving Antiretroviral Treatment at HIV Care and Treatment and Prevention of Mother-To-Child HIV Transmission Sites in Cameroon

The World Health Organization recommends retesting of newly diagnosed HIV cases for verification of results prior to antiretroviral therapy (ART) initiation. This study aimed at ascertaining the HIV status of clients on lifelong ART. We tested 25% of ART clients in 6 care and treatment (C&amp;T) sites and all HIV-positive women receiving ART in 22 prevention of mother-to-child HIV transmission (PMTCT) sites in Northwest and Southwest regions. Testing was proposed consecutively to clients in group education sessions during ART refill visit until the sample size was achieved. Individual counselling was provided to clients who opted to be retested. Testing was with Determine HIV-1/2 and First Response rapid tests and further testing was with DNA-PCR. Clients with negative test results were counseled to discontinue ART. Results were analyzed comparing misdiagnosis at ART and PMTCT sites. A total of 4526 ART clients were retested for HIV; 3914(86.5%) from ART and 612(13.5%) from PMTCT sites. Female participants dominated (79%) and the median age was 39 years. Higher proportions of clients retested at PMTCT sites were negative with both tests (0.8% vs 0.1%) and had discordant results (1.1% vs 0.4%) than at ART sites. All 32 clients with negative or discordant results were tested with DNA-PCR and 22(0.5%) were negative; 11(0.3%) in ART and 11(1.8%) in PMTCT sites. HIV positive status was confirmed for 99.5% of clients retested, with a lower rate at PMTCT (98.2%) than C&amp;T (99.7%) sites; meaning misdiagnosis and inappropriate ART treatment was more likely at PMTCT. Adherence to recommendation for HIV retesting for verification will reduce inappropriate treatment. Keywords: HIV, Retesting, Misdiagnosis, Care and Treatment Centre, PMTCT, Cameroon

High Incidence and Predictors of Loss to Follow-up among Children and Adolescents on Life Long Antiretroviral Therapy in the Conflict-affected Northwest and Southwest Regions of Cameroon: A Retrospective Cohort Study

Background: Retention in care and transition to adulthood are critical for children and adolescents living with HIV on Antiretroviral Therapy (ART) in HIV treatment programs in Sub Sahara, Africa. Objective: This study aimed to determine the incidence and predictors of loss-to-follow-up (LTFU) in the context of the ongoing crisis caused by an armed conflict in the Northwest and Southwest Regions of Cameroon, where staff in HIV treatment programs faced unique challenges of retention of children/adolescents. Methods: We employed a multi-stage mixed method design in which we conducted a retrospective cohort study to determine incidence and risk factors for LTFU through data abstraction from medical records of children and adolescents from five (5) ART treatment centers, followed by seventeen (17) key informant interviews conducted with healthcare workers to gain further insights into the reasons for LTFU among children and adolescents enrolled between January 2018 to December 2021. Kaplan–Meier plots were used to determine the probability of LTFU as a function of time. The Cox regression model was used to measure predictors of LTFU. Endpoint-recorded interviews were transcribed, translated, and analyzed using Atlas-ti Version 9. Results: A total of 1,030 children and adolescents (p-y) were enrolled for follow-up. 138 (13.4%) were LTFU, with an overall incidence rate of 33.0 LTFU per 1000 person years. Survival probability decreased for younger children and older adolescents. Receiving care in a rural health facility (AHR:2.14 (1.23-3.76), non-biological caregivers (AHR: 2.44; 95% CI: 1.59-3.74), short duration on ART, being on a sub-optimal regimen (AHR: 17.83; 95% CI: 11.00-29.00) and long distances to health facility (AHR:2.05; 95% CI: 1.10-3.20) were significant predictors of LTFU. Multiple Caregivers (94.1%), long distances/cost of transportation (88.2%), socio-political crises (75.5%), peer pressure, refusal, dating and marriage among adolescents (70.5%), stigma (64.7%), competitive life activities (58.8%), lack of timely disclosure (53%), poverty/lack of partner/family support (48.2%), lack of understanding on the disease process (47.0%), alternative forms of health care (29.4%), and shortage of ARVs (13.8%) were reasons for poor retention from the interviews. Conclusion: The overall incidence rate of LTFU was 33.0 per 1000 person years for children and adolescents initiated on lifelong ART over a period of four (4) years in the conflict-affected areas. The study portrays the need for innovative, multifaceted strategies to mitigate the predictors of this high-risk LTFU in displaced populations in the context of a sociopolitical crisis.

SARS-CoV-2 seroprevalence among women living with HIV on life-long antiretroviral therapy (ART) and their children in Zimbabwe – PEPFAR-PROMOTE Study

SARS-CoV-2 seroprevalence among women living with HIV on life-long antiretroviral therapy (ART) and their children in Zimbabwe – PEPFAR-PROMOTE Study

Three-year outcomes for women newly initiated on lifelong antiretroviral therapy during pregnancy – Malawi option B+

IntroductionAntiretroviral therapy (ART) is very effective in preventing vertical transmission of HIV but some women on ART experience different virologic, immunologic, and safety profiles. While most pregnant women are closely monitored for short-term effects of ART during pregnancy, few women receive similar attention beyond pregnancy. We aimed to assess retention in care and clinical and laboratory-confirmed outcomes over 3 years after starting ART under Malawi’s Option B + program.MethodsWe conducted a prospective cohort study of pregnant women newly diagnosed with HIV who started tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/3TC/EFV) for the first time at Bwaila Hospital in Lilongwe, Malawi between May 2015 and June 2016. Participants were followed for 3 years. We summarized demographic characteristics, pregnancy outcomes, and clinical and laboratory adverse events findings using proportions. Log-binomial regression models were used to estimate the overall risk ratios (RR) and the corresponding 95% confidence interval (CI) for the association between index pregnancy (i.e. index pregnancy vs. subsequent pregnancy) and preterm birth, and index pregnancy and low birthweight.ResultsOf the 299 pregnant women who were enrolled in the study, 255 (85.3%) were retained in care. There were 340 total pregnancies with known outcomes during the 36-month study period, 280 index pregnancies, and 60 subsequent pregnancies. The risks of delivering preterm (9.5% for index pregnancy and13.5% for subsequent pregnancy: RR = 0.70; 95% CI: 0.32–1.54), or low birth weight infant (9.8% for index pregnancy and 4.2% for subsequent pregnancy: RR = 2.36; 95% CI: 0.58–9.66) were similar between index and subsequent pregnancies. Perinatally acquired HIV was diagnosed in 6 (2.3%) infants from index pregnancies and none from subsequent pregnancies. A total of 50 (16.7%) women had at least one new clinical adverse event and 109 (36.5%) women had at least one incident abnormal laboratory finding. Twenty-two (7.3%) women switched to second line ART: of these 64.7% (8/17) had suppressed viral load and 54.9% (6/17) had undetectable viral load at 36 months.ConclusionMost of the women who started TDF/3TC/EFV were retained in care and few infants were diagnosed with perinatally acquired HIV. Despite switching, women who switched to second line therapy continued to have higher viral loads suggesting that additional factors beyond TDF/3TC/EFV failure may have contributed to the switch. Ongoing support during the postpartum period is necessary to ensure retention in care and prevention of vertical transmission.

Human immunodeficiency virus and antiretroviral therapy-mediated immune cell metabolic dysregulation in children born to HIV-infected women: potential clinical implications.

Commencing lifelong antiretroviral therapy (ART) immediately following HIV diagnosis (Option B+) has dramatically improved the health of HIV-infected women and their children, with the majority being of HIV-exposed children born uninfected (HEU). This success has led to an increasing population of HIV-infected women receiving ART during pregnancy and children exposed to ART in utero. Nonetheless, a small proportion of children are still infected with HIV (HEI) each year. HEI children suffer from reduced immunocompetence and host-defence, due to CD4+ T lymphocyte depletion, but also dysregulation of other immune cells including CD8+ T lymphocytes, natural killer (NK) cells, macrophages including B lymphocytes. Furthermore, although HEU children are uninfected, altered immune responses are observed and associated with increased vulnerability to infections. The mechanisms underlying immune dysregulation in HEU children remain poorly described. Building on early studies, emerging data suggests that HIV/ART exposure early in life affects cell metabolic function of HEU children. Prenatal HIV/ART exposure has been associated with dysregulation of mitochondria, including impaired DNA polymerase activity. Furthermore, dysregulation of oxidative phosphorylation (OXPHOS) causes a decreased generation of adenosine triphosphate (ATP) and increased production of reactive oxygen species (ROS), resulting in oxidative stress. These altered metabolic processes can affect immune cell viability and immune responses. Recent studies have indicated that immune-metabolic dysregulation may contribute to HIV-associated pathogenesis and clinical observations associated with HIV and ART exposure in HEU/HEI children. Given the critical role metabolic processes in immune cell functioning, immune-metabolic dysregulation in HEU and HEI children may have implications in effective host-defence responses against pathogens, as well as efficacy of standard ART regimens and future novel HIV cure approaches in HEI children. At the same time, targeting metabolic pathways of immune cells may provide safer and novel approaches for HIV cure strategies. Here, we review the current literature investigating immune-metabolic dysregulation in paediatric HIV pathogenesis.

Innate Immune Training Enhances the Reactivation of Latently Infected HIV-1 from Monocytic Cell lines

Abstract HIV virus can persist in a latent but activatable chronic state in resting CD4 +T-cells and macrophages that are more persistent, leading to the requirement of lifelong combination antiretroviral therapy (cART). The latency of HIV-1 in macrophage cells is associated with increased chromatin condensation induced by histone methylation at HIV-1 integration sites. Innate immune training of macrophages has been shown to relieve chromosome condensation through epigenetic rewiring. We hypothesized that training of macrophages could enhance the reactivation of HIV-1 by opening the chromatin to facilitate transcription in response to Latency Reversing Agents (LRAs). We used beta-glucan, Syk inhibitor and Rutaecarpine to train the THP89GFP cell line, which is an experimental model for latently infected HIV-1 monocytes. We found that these trained THP89GFP cells have higher transcription of HIV-1 specific genes in response to PMA stimulation. To check the epigenetic changes associated with training in the proviral HIV-1 DNA of THP89GFP, we performed a chromatin immunoprecipitation for the histone mark, H3K27Ac. Consistent with the higher induction of transcription of HIV-1 genes, we observed that multiple regions of the HIV-1 LTR had higher deposition of H3K27Ac in the trained macrophages. Our studies thus show that induction of trained innate immunity may be a viable approach to the reactivation of latently infected HIV-1. This finding supports the hypothesis that innate immune training stimuli could be developed as novel candidates for enhancing reactivation of latently infected HIV-1, which may facilitate elimination of macrophage reservoirs. This work was supported by the Intramural Research Program of NIAID, NIH This work was supported by the Intramural Research Program of NIAID, NIH and Office of AIDS research.

Conserved multiepitope vaccine constructs: A potent HIV-1 therapeutic vaccine in clinical trials.

Despite the success of Antiretroviral Therapy (ART) in preventing HIV-1-associated clinical progression to AIDS, it is unable to eliminate the viral reservoirs and eradicate the HIV-1 infection. Therapeutic vaccination is an alternative approach to alter the HIV-1 infection course. It can induce effective HIV-1-specific immunity to control viremia and eliminate the need for lifelong ART. Immunological data from spontaneous HIV-1 controllers have shown that cross-reactive T-cell responses are the key immune mechanism in HIV-1 control. Directing these responses toward preferred HIV-1 epitopes is a promising strategy in therapeutic vaccine settings. Designing novel immunogens based on the HIV-1 conserved regions containing a wide range of critical T- and B-cell epitopes of the main viral antigens (conserved multiepitope approaches) supplies broad coverage of global diversity in HIV-1 strains and Human Leukocyte Antigen (HLA) alleles. It can also prevent immune induction to undesirable decoy epitopes theoretically. The efficacy of different novel HIV-1 immunogens based on the conserved and/or functional protective site of HIV-1 proteome has been evaluated in multiple clinical trials. Most of these immunogens were generally safe and able to induce potent HIV-1-specific immunity. However, despite these findings, several candidates have demonstrated limited efficacy in viral replication control. In this study, we used the PubMed and ClinicalTrial.gov databases to review the rationale of designing curative HIV-1 vaccine immunogens based on the conserved favorable site of the virus. Most of these studies evaluate the efficacy of vaccine candidates in combination with other therapeutics and/or with new formulations and immunization protocols. This review briefly describes the design of conserved multiepitope constructs and outlines the results of these vaccine candidates in the recent clinical pipeline.

Development and validation of a novel scale for antiretroviral therapy readiness among pregnant women in urban Zambia with newly diagnosed HIV infection

BackgroundWomen who are newly diagnosed with HIV infection during pregnancy may not be ready to immediately initiate lifelong antiretroviral therapy (ART; called Option B +) as is recommended. Lack of “readiness” drives early disengagement from care and undermines prevention of HIV transmission to infants. Several studies have shown high early attrition of women initiating ART in pregnancy. Although poor ART uptake and adherence have been attributed to various factors including stigma, disclosure issues and structural issues, there is no standard way of determining which pregnant woman will face challenges and therefore need additional support. We developed and validated a novel ART readiness tool in Lusaka, Zambia.MethodsThe aim of this study was to develop and validate a tool that could be used to assess how ready a newly diagnosed pregnant woman living with HIV would be to initiate ART on the day of diagnosis. Using a mixed method design, we conducted this study in three public-setting health facilities in Lusaka, Zambia. Informed by qualitative research and literature review, we identified 27 candidate items. We assessed content validity using expert and target population judgment approaches. We administered the 27-item questionnaire to 454 newly diagnosed pregnant women living with HIV, who were enrolled into a randomized trial (trials number NCT02459678). We performed item reduction analysis and used Cronbach’s alpha coefficient of 0.70 as threshold for reliability.ResultsA total of 454 pregnant women living with HIV enrolled in the study between March 2017 and December 2017; 452 had complete data for analysis. The correlation coefficient between the 27 items on the completed ART readiness scale ranged from 0.31 to 0.70 while item discrimination index ranged from -0.01 to 2.38. Sixteen items were selected for the final scale, representing three domains, which we classified as “internalized and anticipated HIV stigma”, “partner support” and “anticipated structural barriers”.ConclusionWe developed and validated a tool that could be used to assess readiness of newly diagnosed women living with HIV to initiate ART. This ART readiness tool could allow clinics to tailor limited resources to pregnant women living with HIV needing additional support to initiate and remain on ART.

A 12-month Prospective Study of HIV-infected and HIV-uninfected Women and Their Infants in Malawi: Comparative Analysis of Clinical Events and Infant Growth.

Few studies have compared clinical outcomes in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) infants in the current scenario of universal and lifelong maternal antiretroviral therapy (ART). HIV-uninfected and HIV-infected Malawian women receiving ART and their breastfed infants were followed for 12 months postpartum, analyzing the rates of infectious and noninfectious events and assessing infant growth at 6 weeks, 6 months, and 12 months. The cohorts included 227 mothers (70 HIV-negative, 157 HIV-positive) and 235 infants (72 HUU, 163 HEU). No maternal or infant deaths occurred during follow-up. HIV-negative women were less likely to complete follow-up (48.6% versus 91.1%). Mothers with and without HIV had similar rates of both infectious and noninfectious events per person-month. Infants who were HEU, compared with HUU, had higher rates of events of any type, lower respiratory tract infections (LRTI), and noninfectious events. HEU had lower body mass index (BMI) at 6 weeks but did not differ from HUU in all anthropometric measures at 6 and 12 months; in growth between 6 weeks and 12 months; and in occurrence of stunting, underweight, and wasting at 6 weeks, 6 months, and 12 months. During the first year of life, infants who were HEU, compared with HUU, showed a transiently lower BMI and an increased risk of LRTI.

Challenges and commonly used countermeasures in the implementation of lifelong antiretroviral therapy for PMTCT in Central Uganda: Health providers' perspective.

Uganda has implemented lifelong antiretroviral therapy for the prevention of mother-to-child HIV transmission since September 2012. Implementation of this strategy has been met with health provider and client challenges which have persisted up to date. This study explored providers' perspectives on the challenges and countermeasures of the implementation and scale-up of lifelong ART among pregnant and breastfeeding women. A qualitative descriptive study was conducted whereby 54 purposively selected participants from six facilities in three districts of Central Uganda namely; Masaka, Mityana, and Luwero were recruited. A key informant interview guide was used to collect data from the study participants. The data were thematically analysed using Atlas-ti, Version 7. Study participants reported challenges under the themes of 1) inadequacy of HIV service delivery (lack of relevant training, health provider shortages, inadequate counselling, stock-outs of essential HIV commodities); 2) Non-utilization of HIV services (Non-disclosure of HIV- positive results, denial of HIV positive results, fear to be followed up, unwillingness to be referred, large catchment area, lack of transport); and 3) Suboptimal treatment adherence (fear of ART side effects, preference for traditional medicines, low male partner involvement in care and treatment). Strategies such as on-job training, mentorship, task shifting, redistribution of HIV commodities across facilities, accompanying of women to mother-baby care points, ongoing counseling of women, peers, and family support groups were commonly used countermeasures. This study highlights key challenges that health providers face in implementing lifelong antiretroviral therapy services among pregnant and postpartum women. Context-specific, innovative, and multilevel system interventions are required at national, district, health facility, community and individual levels to scale up and sustain the lifelong antiretroviral therapy strategy among pregnant and breastfeeding women.