Immediate Initiation Of Antiretroviral Therapy Research Articles

Early antiretroviral therapy and its impact on natural killer cell dynamics in HIV-1 infected men who have sex with men: a cross-sectional pilot study evaluating the impact of early ART initiation on NK cell perturbation in HIV infection.

Phenotypic changes and functional impairment of natural killer (NK) cells occur early in HIV-1 infection. Antiretroviral therapy (ART) effectively restores CD4+ T cell counts and suppresses HIV-1 to undetectable levels. The role and efficacy of immediate ART initiation in mitigating NK cell aberrations remain to be elucidated comprehensively. This study hypothesized that HIV-1 infection negatively influences NK cell evolution and that early ART initiation restores these perturbations. Blood samples were collected longitudinally from five acutely HIV-1 infected men who have sex with men in Nairobi, Kenya. Participants were immediately initiated on ART after HIV-1 diagnosis. Blood samples were drawn pre-infection and at sequential bi-weekly post-infection time points. Peripheral blood mononuclear cells were stained with panel NK cells surface markers to assess HIV-induced phenotypic changes by flow cytometry. Some cells were also stimulated overnight with K562 cell line, IL-2, and IL-15 and stained for flow cytometry functionality. HIV-1 infection was associated with significant reductions in the production of IFN-γ (P = 0.0264), expression of CD69 (P = 0.0110), and expression of NK cell inhibitory receptor Siglec7 (P = 0.0418). We observed an increased NK cell degranulation (P = 0.0100) and an upregulated expression of cell exhaustion marker PD-1 (P = 0.0513) at post-infection time points. These changes mainly were restored upon immediate initiation of ART, except for Siglec7 expression, whose reduced expression persisted despite ART. Some HIV-associated changes in NK cells may persist despite the immediate initiation of ART in acute HIV-1 infections. Our findings suggest that understanding NK cell dynamics and their restoration after ART can offer insights into optimizing HIV-1 treatment and potentially slowing disease progression.IMPORTANCENatural killer (NK) cells play a crucial role in controlling of HIV-1 replication and progression to disease. Perturbations of their functionality may therefore result in deleterious disease outcomes. Previous studies have demonstrated reduced NK cell functionality in chronic HIV-1 infection that positively correlated to HIV-1 viral load. This may suggest that control of HIV-1 viremia in acute HIV-1 infection may aid in enhancing NK cell response boosting the inate immunity hence effective control of viral spread and establishment of viral reservoir. Antiretroviral therapy (ART) effectively supresses HIV-1 viremia to undectable levels and restores CD4+ T cell counts. Our study highlights the significant role of early ART initiation in mitigating NK cell disruptions caused by acute HIV-1 infection. Our results suggest that early initiation of ART could have benefits beyond suppressing viral load and restoring CD4+ T cell counts. In addition, it could boost the innate immunity necessary to control disease progression.

Antiretroviral Regimen and Pregnancy Outcomes of Women Living with HIV in a US Cohort.

Women who are pregnant and living with HIV have traditionally been excluded from clinical trials regarding new pharmacotherapy. Immediate initiation of antiretroviral therapy (ART) is recommended for women who are pregnant and living with HIV. Integrase inhibitors (INSTIs) are first-line recommended agents as they lead to more rapid HIV viral load reduction. We conducted a retrospective study of women who are pregnant and living with HIV who received prenatal care at the University of Washington. Mothers were categorized by ART class: INSTI, protease inhibitors (PI), and non-nucleoside reverse transcriptase inhibitors (NNRTI). Chi-square and t-tests were used for the analysis of baseline characteristics, and generalized estimating equations were used to adjust for HIV viral suppression between groups. There were a total of 234 mother-infant pairs whose pregnancies progressed beyond 20 weeks. The study demonstrated that women on INSTI regimens were more likely to have a shorter time to viral load suppression than women on NNRTI regimens. Additionally, seven congenital anomalies were identified in this cohort, none of which were neural tube defects. There was no perinatal transmission of HIV to any of the infants. This small cohort of women provides high-quality data regarding the safety and efficacy of INSTI use for both mothers and infants in resource-rich settings.

Economics of point-of-care infant HIV tests

Economics of point-of-care infant HIV tests

Predictors of delayed Anti-Retroviral Therapy initiation among adults referred for HIV treatment in Uganda: a cross-sectional study

BackgroundUganda’s current guidelines recommend immediate initiation of Anti-Retroviral Therapy (ART) for persons living with HIV in order to reduce HIV/AIDS related morbidity and mortality. However, not all eligible PLHIV initiate ART within the recommended time following HIV diagnosis. We assessed the prevalence and factors associated with delayed ART initiation among PLHIV referred for ART initiation, five years since rolling out the test and treat guidelines.MethodsIn this cross-sectional study, we enrolled adult patients referred to Mulago Immune Suppressive Syndrome (Mulago ISS) clinic for ART initiation from January 2017 to May 2021. We collected data on socio-demographics, HIV diagnosis and referral circumstances, and time to ART initiation using a questionnaire. The outcome of interest was proportion of patients that delayed ART, defined as spending more than 30 days from HIV diagnosis to ART initiation. We performed multivariable logistic regression and identified significant factors.ResultsA total of 312 patients were enrolled of which 62.2% were female. The median (inter-quartile range [IQR]) age and baseline CD4 count of the patients were 35 (28–42) years and 315 (118.8–580.5) cells/μL respectively. Forty-eight (15.4%) patients delayed ART initiation and had a median (IQR) time to ART of 92 (49.0–273.5) days. The factors associated with delayed ART initiation were; 1) having had the HIV diagnosis made from a private health facility versus public, (adjusted odds ratio [aOR] = 2.4 (95% confidence interval [CI] 1.1–5.5); 2) initial denial of positive HIV test results, aOR = 5.4 (95% CI: 2.0–15.0); and, 3) having not received a follow up phone call from the place of HIV diagnosis, aOR = 2.8 (95% CI: 1.2–6.8).ConclusionThere was significant delay of ART initiation among referred PLHIV within 5 years after the rollout of test and treat guidelines in Uganda. Health system challenges in the continuity of HIV care services negatively affects timely ART initiation among referred PLHIV in Uganda.

Cost-effectiveness analysis of 'test and treat' policy for antiretroviral therapy among heterosexual HIV population in India.

The World Health Organisation recommended immediate initiation of antiretroviral therapy (ART) in all adult human immunodeficiency virus (HIV) patients regardless of their CD4 cell count. This study was undertaken to ascertain the cost-effectiveness of implementation of these guidelines in India. A Markov model was developed to assess the lifetime costs and health outcomes of three scenarios for initiation of ART treatment at varying CD4 cell count <350/mm[3], <500/mm[3] and test and treat using health system perspective using life-time horizon. A few input parameters for this model namely, transition probabilities from one stage to another stage of HIV and incidence rates of TB were calculated from the data of Centre of Excellence for HIV treatment and care, Chandigarh; whereas, other parameters were obtained from the published literature. Total HIV-related deaths averted, HIV infections averted and incremental cost-effectiveness ratio per quality adjusted life years (QALYs) gained were calculated. Test and treat intervention slowed down the progression of disease and averted 18,386 HIV-related deaths, over lifetime horizon. It also averted 16,105 new HIV infections and saved 343,172 QALYs as compared to the strategy of starting ART at CD4 cell count of 500/mm[3]. Incremental cost per QALY gained for the immediate initiation of ART as compared to ART at CD4 cell count of 500/mm[3] and 350/mm[3] was ₹ 46,599 and 80,050, respectively at reported rates of adherence to the therapy. Immediate ART (test and treat) is highly cost-effective strategy over the past criteria of delayed therapy in India. Cost-effectiveness of this policy is largely because of reduction in the transmission of HIV.

Utility of the Signal-to-Cutoff Ratio and Antigen Index from Fourth- and Fifth-Generation HIV-1/HIV-2 Antigen/Antibody Assays for the Diagnosis of Acute HIV Infection: Applicability for Real-Time Use for Immediate Initiation of Antiretroviral Therapy.

Identification of individuals with acute HIV infection (AHI) and rapid initiation of antiretroviral therapy (ART) are priorities for HIV elimination efforts. Fourth- and fifth-generation HIV-1/HIV-2 antigen (Ag)/antibody (Ab) combination assays can quickly identify patients with AHI, but false-positive results can occur. Confirmatory nucleic acid amplification testing (NAAT) may not be rapidly available. We reviewed the data for 127 patients with positive fourth-generation ARCHITECT and fifth-generation Bio-Plex immunoassay results who had negative or indeterminate confirmatory Ab testing results, which yielded 38 patients with confirmed AHI and 89 patients with false-positive results. The receiver operating characteristic (ROC) curves showed excellent discriminatory power, with an area under the curve (AUC) for the signal-to-cutoff (S/CO) ratio of 0.970 (95% confidence interval [CI], 0.935 to 1.00) and an AUC for the Ag index (AI) of 0.968 (95% CI, 0.904 to 1.00). A threshold of 3.78 for the S/CO ratio would maximize the sensitivity (96.3%) and specificity (93.4%). The threshold for AI was 2.83 (sensitivity of 100% and specificity of 96.4%). The S/CO ratio was significantly correlated with the viral load (Spearman correlation coefficient, 0.486 [P = 0.014]), but the AI was not. The viral loads were all high, with a median of >2.8 million copies/mL. Two false-positive results with AI and S/CO ratio values markedly higher than the medians were observed, indicating that biological false-positive results can occur. Review of the S/CO ratio or AI may be used to improve the accuracy of AHI diagnosis prior to confirmatory NAAT results being available.

A Randomized Trial of Point-of-Care Early Infant Human Immunodeficiency Virus (HIV) Diagnosis in Zambia.

BackgroundPoint-of-care (POC) early infant diagnosis (EID) provides same-day results and the potential for immediate initiation of antiretroviral therapy (ART).MethodsWe conducted a pragmatic trial at 6 public clinics in Zambia. HIV-exposed infants were individually randomized to either (1) POC EID (onsite testing with the Alere q HIV-1/2 Detect) or (2) enhanced standard of care (SOC) EID (off-site testing at a public laboratory). Infants with HIV were referred for ART and followed for 12 months. Our primary outcome was defined as alive, in care, and virally suppressed at 12 months.ResultsBetween March 2016 and November 2018, we randomized 4000 HIV-exposed infants to POC (n=1989) or SOC (n=2011). All but 2 infants in the POC group received same-day results, while the median time to result in the SOC group was 27 (interquartile range: 22–30) days. Eighty-one (2%; 95% confidence interval [CI]: 1.6–2.5%) infants were diagnosed with HIV. Although ART initiation was high, there were 15 (19%) deaths, 15 (19%) follow-up losses, and 31 (38%) virologic failures. By 12 months, only 20 of 81 (25%; 95% CI: 15–34%) infants with HIV were alive, in care, and virally suppressed: 13 (30%; 16–43%) infants in the POC group vs 7 (19%; 6–32%) in the SOC group (RR: 1.56; .7–3.50).ConclusionsPOC EID eliminated diagnostic delays and accelerated ART initiation but did not translate into definitive improvement in 12-month outcomes. In settings where centralized EID is well functioning, POC EID is unlikely to improve pediatric HIV outcomes.Clinical Trials RegistrationThis trial is registered at https://clinicaltrials.gov (NCT02682810).

Risk for Non-AIDS-Defining and AIDS-Defining Cancer of Early Versus Delayed Initiation of Antiretroviral Therapy : A Multinational Prospective Cohort Study.

Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500×109 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. To estimate the long-term risk difference for cancer with the immediate ART strategy. Multinational prospective cohort study. The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States. 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016). The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts <350 and <500×109 cells/L) ART initiation strategies. During 64021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500×109 cells/L and less than 350×109 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. Potential residual confounding due to observational study design. In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer. Highly Active Antiretroviral Therapy Oversight Committee.

Annals for Educators - June 2021.

Annals for Educators - June 2021.

Impact of immediate initiation of antiretroviral therapy among men who have sex with men infected with HIV in Chengdu, southwest China: trends analysis, 2008\u20132018

BackgroundGiven the rampant HIV epidemic among men who have sex with men (MSM) in Chengdu, southwest China, Treat All policy, defined as immediate antiretroviral therapy (ART) initiation after HIV diagnosis, was implemented since 2014. Real-world research evaluating impacts of immediate ART on HIV epidemics is needed to optimize policy-making as national and international guidelines have been lowering ART eligibility threshold. The purpose of this study is to: assess temporal trends of the HIV epidemic and impacts of Treat All policy among MSM; and lay foundation for HIV-related policy evaluation using longitudinal routine data from health information systems.MethodsData used in this study were HIV sentinel seroprevalence, annual reported HIV cases and ART coverage rate among MSM in Chengdu from 2008 to 2018, derived from national HIV/AIDS information system. Temporal trends of the HIV epidemic were described using Joinpoint Regression Program. Interrupted time-series method was deployed to evaluate Treat All policy.ResultsHIV sentinel seroprevalence rose from 11.20% in 2008 to 17.67% in 2013 and Annual Percent Change (APC) was 8.25% (95% CI − 2.40%, 20.07%), then decreased to 5.17% in 2018 (APC = − 19.63%, 95% CI − 27.54%, − 10.86%). Newly reported HIV cases increased from 168 cases in 2008 to 1232 cases in 2015 (APC = 26.99%, 95% CI 21.32%, 32.93%), and reduced to 1014 cases in 2018 (APC = − 8.80%, 95% CI − 18.45%, 2.01%). ART coverage rate has been climbing from 11.11% in 2008 to 92.29% in 2018 and Average Annual Percent Change was 16.09% (95% CI 11.76%, 20.59%). Results of interrupted time-series models showed that compared to an annual increase of 0.87% during pre-policy period, there was a decline of 3.08% (95% CI − 0.0366%, − 0.0250%) per year of HIV sentinel seroprevalence since 2014; and compared to an annual increase of 116 cases before 2014, there was an annual drop of 158 newly reported HIV cases (95% CI − 194.87%, − 121.69%) during the post-policy period.ConclusionsImmediate ART after HIV diagnosis could potentially curb HIV transmission at population level among MSM, along with other strategies. Future assessment of HIV prevention and control policy can be carried out using routinely collected longitudinal data from health information systems.

The Impact of Immediate Initiation\xa0of\xa0Antiretroviral Therapy on Patients' Healthcare Expenditures: A Stepped-Wedge Randomized Trial in Eswatini

Immediate initiation of antiretroviral therapy (ART) for all people living with HIV has important health benefits but implications for the economic aspects of patients' lives are still largely unknown. This stepped-wedge cluster-randomized controlled trial aimed to determine the causal impact of immediate ART initiation on patients’ healthcare expenditures in Eswatini. Fourteen healthcare facilities were randomly assigned to transition at one of seven time points from the standard of care (ART eligibility below a CD4 count threshold) to the immediate ART for all intervention (EAAA). 2261 patients living with HIV were interviewed over the study period to capture their past-year out-of-pocket healthcare expenditures. In mixed-effects regression models, we found a 49% decrease (RR 0.51, 95% CI 0.36, 0.72, p < 0.001) in past-year total healthcare expenditures in the EAAA group compared to the standard of care, and a 98% (RR 0.02, 95% CI 0.00, 0.02, p < 0.001) decrease in spending on private and traditional healthcare. Despite a higher frequency of HIV care visits for newly initiated ART patients, immediate ART initiation appears to have lowered patients’ healthcare expenditures because they sought less care from alternative healthcare providers. This study adds an important economic argument to the World Health Organization’s recommendation to abolish CD4-count-based eligibility thresholds for ART.

Mortality in relation to hepatitis B virus (HBV) infection status among HIV-HBV co-infected patients in sub-Saharan Africa after immediate initiation of antiretroviral therapy.

It is unknown how past and active hepatitis B virus (HBV) infection affect immunorecovery and mortality in people with HIV who initiate tenofovir-based antiretroviral therapy (ART). Using data collected between 2008 and 2015, we studied people with HIV in sub-Saharan Africa initiating immediate ART in the Temprano randomized control trial. We classified participants into HBV groups at ART initiation: hepatitis B surface antigen (HBsAg)-positive with HBV DNA≥2,000IU/ml; HBsAg-positive with HBV DNA<2,000IU/ml; isolated HBcAb-positive; resolved infection (HBsAb-positive/HBcAb-positive); and HBV non-immune/vaccinated (HBcAb-negative). We compared square-root CD4-cell count increases using mixed-effect, non-linear regression adjusted for age, sex, baseline CD4 cell count, and HIV RNA. We compared all-cause mortality using Bayesian parametric survival regression. Among 879 participants, 24 (2.7%) had HBsAg with high HBV DNA, 76 (8.6%) HBsAg with low HBV DNA, 325 (37.0%) isolated anti-HBcAb, 226 (25.7%) resolved HBV infection and 228 (25.9%) HBV non-immune/vaccinated. We found no significant difference in CD4 cell increases between HBV-infection groups after adjustment (p=0.16). Participants with HBsAg and high HBV DNA had the highest incidence of all-cause mortality (1.9/100 person-years, 95% Credibile Interval [CrI]=1.0-3.4). By comparison, incidence rates of mortality were reduced by 57% (95%CrI=-79%, -13%), 60% (95%CrI=-82%, -12%) and 66% (95%CrI=-84%, -23%) in those who had isolated anti-HBcAb-positive, resolved HBV infection and HBV non-immune/vaccinated, respectively. In conclusion, individuals with HIV and past HBV infection or isolated anti-HBcAb-positive serology, much like HBV non-immune/vaccinated, experience lower mortality than those with HBsAg and high HBV DNA. Additional HBV-related management would not be necessary for these individuals.

A Journey of Hope: giving research participants a voice to share theirexperiences and improve community engagement aroundadvanced HIV disease in Uganda.

Over the last decade excellent progress has been made globally in HIV management thanks to antiretroviral therapy (ART) rollout and international guidelines now recommending immediate initiation of ART in people living with HIV. Despite this, advanced HIV disease (CD4 less than 200 cells/mL) and opportunistic infections remain a persistent challenge and contribute significantly to HIV-associated mortality, which equates to 23,000 deaths in Uganda in 2018 alone. Our Meningitis Research Team based in Uganda is committed to conducting clinical trials to answer important questions regarding diagnostics and management of HIV-associated opportunistic infections, including tuberculosis and cryptococcal meningitis. However, clinical research is impossible without research participants and results are meaningless unless they are translated into benefits for those affected by the disease. Therefore, we held a series of community engagement events with the aims of 1) giving research participants a voice to share their experiences of clinical research and messages of hope around advanced HIV disease with the community, 2) dispelling myths and stigma around HIV, and 3) raising awareness about the complications of advanced HIV disease and local clinical research and recent scientific advances. The purpose of this Open Letter is to describe our community engagement experience in Uganda, where we aimed to give clinical research participants a greater voice to share their experiences.These activities build upon decades of work in HIV community engagement and lays a platform for future research and engagement activities.

Impact of Immediate ART Initiation and Patient Health Expenditures: A Stepped-Wedge Randomised Trial

Abstract Background Healthcare expenditures for HIV care pose a major economic burden on households in sub-Saharan Africa. While immediate initiation of antiretroviral therapy (ART) for all HIV-positive patients has important health benefits, it is unknown how this profound change in HIV care provision will affect patients' healthcare expenditures. This study, therefore, aims to determine the causal impact of immediate ART initiation on patients' healthcare expenditures in Eswatini. Methods This stepped-wedge cluster-randomised controlled trial enrolled fourteen public-sector healthcare facilities in rural and semi-urban Eswatini. Facilities were randomly assigned to transition at one of seven time points from the standard of care (ART eligibility at CD4 counts of &amp;lt; 500 cells/mm3) to the immediate ART for all intervention (EAAA). The primary outcome was total patient-borne healthcare expenditures during the preceding 12 months. We used mixed-effects negative binomial regressions adjusted for secular trends and clustering at the facility level. Results 2261 participants were interviewed over the study period. Participants in the EAAA phase reported a 45% decrease (RR: 0.55, 95% CI: 0.39, 0.77, p &amp;lt; 0.001) in their total past-year healthcare expenditures compared to the standard-of-care phase. Patients' healthcare expenditures for private and traditional healthcare providers were 93% (RR 0.07, 95% CI: 0.01, 0.77, p &amp;lt; 0.001) lower in the EAAA than the standard of care phase. Self-reported health status was similar between study phases. Conclusions Despite a higher frequency of HIV care visits for newly initiated ART patients, immediate ART initiation lowered patients' healthcare expenditures because they sought less care from private and traditional healthcare providers. This study adds an important economic argument to the World Health Organisation's recommendation for countries to abolish CD4-count-based eligibility thresholds for ART. Key messages This is the first experimental study to examine the impact of immediate ART initiation on patients’ healthcare expenditures and thus obtain a causal estimate of the economic benefits of immediate ART. Immediate ART initiation in Eswatini reduced HIV patients’ healthcare expenditures, at least partially through decreasing care-seeking from traditional and private healthcare providers.

A stepped-wedge randomised trial on the impact of early ART initiation on HIV-patients' economic outcomes in Eswatini.

Since 2015, the World Health Organisation (WHO) recommends immediate initiation of antiretroviral therapy (ART) for all HIV-positive patients. Epidemiological evidence points to important health benefits of immediate ART initiation; however, the policy’s impact on the economic aspects of patients' lives remains unknown. We conducted a stepped-wedge cluster-randomised controlled trial in Eswatini to determine the causal impact of immediate ART initiation on patients’ individual- and household-level economic outcomes. Fourteen healthcare facilities were non-randomly matched into pairs and then randomly allocated to transition from the standard of care (ART eligibility at CD4 counts of <350 cells/mm3 until September 2016 and <500 cells/mm3 thereafter) to the ‘Early Initiation of ART for All’ (EAAA) intervention at one of seven timepoints. Patients, healthcare personnel, and outcome assessors remained unblinded. Data were collected via standardised paper-based surveys with HIV-positive adults who were neither pregnant nor breastfeeding. Outcomes were patients’ time use, employment status, household expenditures, and household living standards. A total sample of 3019 participants were interviewed over the duration of the study. The mean number of participants approached at each facility per time step varied from 4 to 112 participants. Using mixed-effects negative binomial regressions accounting for time trends and clustering at the level of the healthcare facility, we found no significant difference between study arms for any economic outcome. Specifically, the EAAA intervention had no significant effect on non-resting time use (RR = 1.00 [CI: 0.96, 1.05, p=0.93]) or income-generating time use (RR = 0.94, [CI: 0.73,1.20, p=0.61]). Employment and household expenditures decreased slightly but not significantly in the EAAA group, with risk ratios of 0.93 [CI: 0.82, 1.04, p=0.21] and 0.92 [CI: 0.79, 1.06, p=0.26], respectively. We also found no significant treatment effect on households’ asset ownership and living standards (RR = 0.96, [CI 0.92, 1.00, p=0.253]). Lastly, there was no evidence of heterogeneity in effect estimates by patients’ sex, age, education, timing of HIV diagnosis and ART initiation. Our findings do not provide evidence that should discourage further investments into scaling up immediate ART for all HIV patients. Funded by the Dutch Postcode Lottery in the Netherlands, Alexander von Humboldt-Stiftung (Humboldt-Stiftung), the Embassy of the Kingdom of the Netherlands in South Africa/Mozambique, British Columbia Centre of Excellence in Canada, Doctors Without Borders (MSF USA), National Center for Advancing Translational Sciences of the National Institutes of Health and Joachim Herz Foundation. NCT02909218 and NCT03789448.

A Journey of Hope: giving research participants a voice to share their experiences and improve community engagement around advanced HIV disease in Uganda

Over the last decade excellent progress has been made globally in HIV management thanks to antiretroviral therapy (ART) rollout and international guidelines now recommending immediate initiation of ART in all HIV-positive people. Despite this, advanced HIV disease (CD4 less than 200 cells/mL) and opportunistic infections remain a persistent challenge and contribute significantly to HIV-associated mortality, which equates to 23,000 deaths in Uganda in 2018 alone. Our Meningitis Research Team based in Uganda is committed to conducting clinical trials to answer important questions regarding diagnostics and management of HIV-associated opportunistic infections, including tuberculosis and cryptococcal meningitis. However, clinical research is impossible without research participants and results are meaningless unless they are translated into benefits for those affected by the disease. Therefore, we held a series of community engagement events with the aims of giving clinical research participants a voice in sharing their experiences of clinical research and messages of hope around advanced HIV disease with the community, dispelling myths and stigma around HIV, raising awareness about the complications of advanced HIV disease and local ongoing clinical research and recent scientific advances. The purpose of this Open Letter is to describe our community engagement experience in Uganda, which we hope will lay the foundation for further clinical research public engagement activities, giving research participants a greater voice to share their experiences.

Examining Correlates of Pre-ART and Early ART Adherence to Identify Key Factors Influencing Adherence Readiness.

Although current standard of care for HIV typically involves immediate initiation of antiretroviral therapy (ART), most patients can benefit from first assessing adherence readiness and addressing any barriers to optimal adherence. A sample of 176 HIV patients planning to start ART enrolled in a controlled trial of an adherence intervention that was based on the Information Motivation and Behavioral skills (IMB) model of health behavior. We examined correlates of multiple adherence readiness measures, as well as electronically measured early ART adherence, to identify variables most important for readiness to adhere well at the start of treatment. Education level, recency of HIV diagnosis and knowledge and commitment to adherence were found to be associated with both ART readiness and early ART adherence. These findings suggest that resources to support adherence readiness should target more experienced HIV patients, and strive to bolster knowledge and attitudes that reinforce commitment to adherence.

Impact of immediate initiation of antiretroviral therapy on HIV patient satisfaction.

Immediate ART (or early access to ART for all, EAAA) is becoming a national policy in many countries in sub-Saharan Africa. It is plausible that the switch from delayed to immediate ART could either increase or decrease patient satisfaction with treatment. A decrease in patient satisfaction would likely have detrimental consequences for long-term retention and adherence, in addition to the value lost because of the worsening patient experience itself. We conducted a pragmatic stepped-wedge cluster-randomized controlled trial (SW-cRCT) to determine the causal impact of immediate treatment for HIV on patient satisfaction. This seven-step SW-cRCT took place in 14 public-sector health facilities in Eswatini's Hhohho region, from September 2014 to August 2017. During each step of the trial, we randomly selected days for data collection at each study facility. During these days, a random sample of HIV patients were selected for outcome assessment. In total, 2629 patients provided data on their overall patient satisfaction and satisfaction with the following four domains of the patient experience using a five-point Likert scale: wait time, consultation time, involvement in treatment decisions, and respectful treatment. Higher values on the Likert scale indicated lower patient satisfaction. We analyzed the data using a multilevel ordered logistic regression model with individuals at the first level and health facilities at the second (cluster) level. The proportional odds ratio (OR) comparing EAAA to control was 0.91 (95% CI 0.66-1.25) for overall patient satisfaction. For the specific domains of the patient experience, the ORs describing the impact of EAAA on satisfaction were 1.04 (95% CI 0.61-1.78) for wait time, 0.90 (95% CI 0.62-1.31) for involvement in treatment decisions, 0.86 (95% CI 0.61-1.20) for consultation time, and 1.35 (95% CI 0.93-1.96) for respectful treatment. These results were robust across a wide range of sensitivity analyses. Over time - and independent of EAAA - we observed a worsening trend for both overall patient satisfaction and satisfaction in the four domains of the patient experience we measured. Our findings support the policy change from delayed to immediate ART in sub-Saharan Africa. Immediate (versus delayed) ART in public-sector health facilities in Eswatini had no effect on either overall patient satisfaction or satisfaction with four specific domains of the patient experience. At the same time, we observed a strong secular trend of decreasing patient satisfaction in both the intervention and the control arm of the trial. Further implementation research should identify approaches to ensure high patient satisfaction as ART programs grow and mature.

A Randomised Trial of Point-of-Care Early Infant HIV Diagnosis

Background: Early infant diagnosis (EID) of HIV is critical to the care of the 1.3 million infants who are perinatally exposed to the virus each year. Point-of-care (POC) EID provides same-day results and the potential for improved survival through immediate initiation of antiretroviral therapy (ART). Methods: We conducted a pragmatic randomised trial at 6 primary health centres in Lusaka, Zambia. HIV-exposed infants were equally allocated to either: (a) POC EID – on-site testing with the Alere q HIV-1/2 Detect instrument or (b) enhanced standard of care (SOC) EID – off-site testing at a public-sector laboratory. We provided a safety net if off-site EID results did not return within 4 weeks. Infants found to be HIV infected were immediately referred for care in the public sector and followed by the study for 12 months. Our primary outcome was programmatic success, defined as being alive, in care, and virally suppressed (<200 copies/mL) at 12 months. We also compared the time to receipt of result by the facility and by the participant’s parent/guardian. Findings: Between March 2016 and November 2018, we randomised 4,000 HIV-exposed infants at a median age of 6.4 weeks to POC (n=1,989) or enhanced SOC (n=2,011). All but 2 infants in the POC group received same-day results, while the median time to result in the SOC group was 27 (IQR: 22-30) days. Most infants randomised to SOC relied on the trial’s diagnostic safety net. Eighty-one (2%, 95% CI: 1.6–2.5%) infants were diagnosed with HIV. Although ART initiation was high overall, there were 15 (19%) deaths, 15 (19%) follow-up losses, and 31 (38%) virologic failures during follow-up. By 12 months, only 20 of 81 (25%, 95% CI: 15–34%) HIV-infected infants were alive, in care, and virally suppressed: 13 (30%, 95% CI: 16–43%) infants in the POC group vs. 7 (19%, 95% CI: 6–32%) in the enhanced SOC group (RR: 1.56, 95% CI: 0.7–3.50). Interpretation: Outcomes among HIV-infected infants were poor in both randomization groups. Although POC EID eliminated diagnostic delays and accelerated ART initiation, the POC EID strategy did not translate into a statistically significant improvement in programmatic success. Our findings are limited by a lower than anticipated number of HIV-infected infants in the trial, a welcome consequence of the success of Zambia’s perinatal HIV prevention program. Trial Registration: This trial is registered at https://clinicaltrials.gov (NCT02682810). Funding Statement:This research was funded by the U.S. National Institutes of Health (NIH) (U01AI100053). Biostatistical and laboratory support was provided by the UNC Center for AIDS Research, which is supported in part by the NIH (P30AI050410). Additional investigator and trainee support was provided by the NIH for BHC (K24AI120796) and CEF (T32HD075731, D43TW009340). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Ethical approval for the trial (NCT02682810) was granted by the University of Zambia Biomedical Research Ethics Committee (BREC Ref: 010-02-13), the Zambian Ministry of Health, and the University of North Carolina at Chapel Hill Institutional Review Board (IRB Number: 12-1346).

Monitoring HIV infection in Minas Gerais state: 15-year assessment of adults living with HIV initiating Antiretroviral Therapy.

INTRODUCTION The first Brazilian HIV treatment recommendation was put forward in 1996, resulting in 12 subsequent guidelines. Several changes were made regarding “when” and “how” to begin treatment. The latest guideline recommends immediate initiation of antiretroviral therapy (ART). This study aimed to describe the evolution of HIV treatment among people living with HIV (PLHIV) who initiated ART between 2004 and 2018 based on the national guideline recommendations concerning T-CD4+ and VL measurements. METHODS A cross-sectional analysis of data of PLHIV aged >18 years, in Minas Gerais who received ART between 2004 and 2018 was conducted. Clinical, therapeutic, and demographic information were obtained from national healthcare databases. The study was divided into four periods: 2004-2007, 2008-2012, 2013-2016, and 2017-2018. Descriptive analyses were performed. RESULTS A total of 60,618 PLHIV initiated ART (67% male and 48% aged 25-39 years), 36% of whom had CD4 counts at ART initiation and 51% documented VL after ART initiation. The median CD4 count ranged from 288 to 373 cells/µL. The median time to ART initiation decreased from 604 to 28 days and was lower among males (p <0.01). The median time from ART initiation to the first VL result decreased from 101 to 62 days over the study period, while the median VL after ART initiation ranged from 2.3 to 1.7 log10 copies/ml. CONCLUSIONS Although our results demonstrated that most recommendations were followed, there seemed to be little impact on CD4 counts and VL testing. This may result in an inadequate evaluation of ART effectiveness.