Late Antiretroviral Therapy Research Articles

Estimating the Effect of COVID-19 Pandemic Restrictions on Self-reported Antiretroviral Therapy Use and Late Refill Visits Among People Living With HIV in Rural South Africa.

People living with HIV require reliable access to and adequate supply of antiretroviral therapy (ART) for viral suppression. The Deliver Health Study, a randomized trial conducted during the COVID-19 pandemic, found that home-delivered ART significantly increased viral suppression compared with clinic-based care. The effect of changing COVID-19 alert levels on self-reported ART use has not been quantified. KwaZulu-Natal, South Africa. Adults living with HIV were followed in the Deliver Health Study during October 2019-December 2020. We used difference-in-differences (DiD) to estimate the effect of changing COVID-19 alert levels during 3 distinct periods on self-reported missed ART doses (missed 0 vs. ≥1 doses in past week) for participants receiving home-delivered vs. clinic-based refills. We additionally estimated the effect of changing COVID-19 alert levels on late clinic ART refill visits (late vs. on-time). We used relative risk regression for both binary outcomes. Of 155 participants, 46% were women and the median age was 36 years. The mean number of missed weekly doses was 0.11, 0, and 0.12 in the home-delivery group and 0.09, 0.08, and 0.18 in the clinic group during periods 1, 2, and 3, respectively. There were no differences in relative risk of self-reported daily ART use between refill groups when comparing across periods [DiDperiod 2 vs. 1 = 1.05; 95% confidence interval: 0.97, 1.13 and DiDperiod 3 vs. 2 = 0.99; 95% confidence interval (CI): 0.91, 1.08]. In the clinic group, the risk of late refill visits was significantly higher during COVID-19 restrictions (vs. before alert level 5 implementation) and even after the COVID-19 alert level was downgraded to level 1 (RRperiod 2 vs. 1 = 1.83, 95% CI: 1.34, 2.51 and RRperiod 3 vs. 2 = 1.71; 95% CI: 1.43, 2.04). The COVID-19 pandemic did not differentially impact self-reported ART adherence by the method of ART refills, but the risk of late clinic refill visits was significantly higher during COVID-19 restrictions and sustained after restrictions were loosened.

Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques

While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings.

Trends and the associated factors of optimal immunological response and virological response in late anti-retroviral therapy initiation HIV cases in Taiwan from 2009 to 2020

BackgroundLate cART initiation (CD4 count ≤200 cells/μL or AIDS-defining opportunistic illnesses [AOIs] at cART initiation) impedes CD4 count recovery and virologic suppression after cART initiation. However, studies to evaluate trends of and modifiable factors for optimal immunological response (IR) and virological response (VR) in people living with HIV (PLWH) with late cART initiation with the current HIV treatment strategies are limited. MethodsWe retrospectively identified 475 PLWH with late cART initiation in 2009–2020. Patients were grouped based on the presence of IR (CD4 count ≥200 cells/μL) or VR (plasma viral load [PVL] ≤ 50 copies/mL) within 18 months after cART initiation (403 [84.8%] IR(+) and 72 [15.2%] IR(−); 422 [88.8%] VR(+) and 53 [11.2%] VR(−)). We used Joinpoint regression to identify IR (+) and VR(+) proportion changes. ResultsFrom 2009 to 2020, the proportion of IR(+) patients remained unchanged (75% to 90%, P = 0.102), whereas that of VR(+) patients increased significantly (75% to 95%, P = 0.007). No join point was identified for either IR(+) or VR(+), and the annual percentage change was 0.56% (nonsignificant) and 1.35% (significant) for IR(+) and VR(+), respectively. Compared to IR(−) patients, IR(+) patients were more likely to have a higher pre-cART PVL, to start with a first-line INSTI-based regimen, or to start cART within 14 days of HIV diagnosis but were less likely to have chronic kidney disease, composite AOIs, or a lower pre-cART CD4 count. Compared to VR(−) patients, VR(+) patients were more likely to start a single-tablet regimen but were less likely to have a higher pre-cART PVL. ConclusionsOur study identified several modifiable factors for optimal IR (rapid cART initiation and INSTI-based regimen initiation) and for optimal VR (STR initiation) among late initiators, which may guide early treatment modifications to reduce their AIDS-defining event incidence and mortality.

Latency to initiation of antiretroviral therapy in people living with HIV in Japan

Rapid initiation of antiretroviral therapy (ART) in HIV infection is recommended because it increases care retention rate and reduces the time to viral suppression. In Japan, although ART initiation is delayed, there is little information on the latency to ART initiation (time from HIV diagnosis to ART initiation). The present study was designed to obtain information on the latency to ART initiation in individuals with 1) acute or recent HIV infection (ARH), and with 2) advanced HIV diseases. Questionnaires were sent to 379 regional AIDS facilities requesting information on the people living with HIV (PLWH) who visited their facilities during 2020. Among 1098 new PLWH visitors, 706 were treatment-naïve patients, including 111 (15.7%) with ARH and 304 (43.1%) with advanced HIV diseases. Among those with ARH, only 8.2% received rapid ART initiation (latency to ART <2 weeks) and the time from diagnosis to virological suppression was longer than 14 weeks in 40.4%. Among those with advanced HIV diseases, 36.2% received late ART initiation (latency to ART ≧6 weeks). Our data showed that only a small proportion of PLWH with ARH in Japan received rapid ART. Furthermore, in PLWH with advanced HIV diseases in Japan, current latency to ART seems too long, though the timing of ART commencement should be tailored according to the presence/lack of opportunistic infections and accessibility to medical care. Further investigation is required to identify barriers to rapid ART initiation in Japan.

Early Antiretroviral Therapy Reduces Severity but Does Not Eliminate Neurodevelopmental Compromise in Children With HIV.

Early antiretroviral therapy (ART) during infancy reduces cognitive impairment due to HIV, but the extent of benefit is unclear. Children were recruited from hospital and health centers providing HIV care and treatment in Nairobi, Kenya. Cognitive, behavioral, and motor outcomes were assessed in children with HIV and early ART (<1 year), children with HIV and late ART (1.5-6 years), and children HIV-unexposed uninfected (CHUU). Domain z scores and odds neurobehavioral impairment (≤15th percentile in CHUU) were compared in adjusted analyses. Children with HIV initiated ART at median ages 0.4 (early ART) and 3.5 years (late ART). Children were assessed at median ages 6.9 (CHUU, N = 61), 6.9 (early ART, N = 54), and 13.5 (late ART; N = 27) years. Children with late ART vs. children with early ART had significantly lower z scores in 7 domains, specifically global cognition, short-term memory, visuospatial processing, learning, nonverbal test performance, executive function, and motor skills (adjusted mean differences, -0.42 to -0.62, P values ≤ 0.05), and had higher odds impairment in 7 domains (adjusted odds ratios [aORs], 2.87 to 16.22, P values ≤ 0.05). Children with early ART vs. CHUU had lower z scores in 5 domains (global cognition, short-term memory, delayed memory, processing speed, and behavioral regulation [adjusted mean differences, -0.32 to -0.88, P values < 0.05]) and higher impairment for 2 domains (short-term memory [aOR, 3.88] and behavioral regulation [aOR 3.46], P values < 0.05). Children with late ART vs. CHUU had lower z scores in 8 domains (adjusted mean differences, -0.57 to -1.05, P values ≤ 0.05), and higher impairment in 7 domains (aORs 1.98 to 2.32, P values ≤ 0.05). Early ART in the first year of life attenuates but does not eliminate the neurodevelopmental compromise of HIV.

Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study.

Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings. Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33-44) years; the median CD4+ T-cell count, 19/μL (10-56/μL); and median HIV viral load, 5.3 (4.9-5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64-2.56) and 1.40 (.66-2.95), respectively. We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.

Kaposi sarcoma-associated herpesvirus, HIV-1 and Kaposi sarcoma risk in black South Africans diagnosed with cancer during antiretroviral treatment rollout.

Kaposi sarcoma-associated herpesvirus (KSHV) causes Kaposi sarcoma (KS). The risk of KS is amplified in HIV-immunosuppressed individuals and antiretroviral therapy (ART) reduces KS incidence. Reliable data on the relationship between these factors are lacking in Africa. We used questionnaires and serum from 7886 black South Africans (18-74 years) with incident cancer, recruited between 1995 and 2016. ART rollout started in 2004. We measured associations between KS, HIV-1 and KSHV before and after ART rollout. We measured seropositivity to HIV-1, KSHV latency-associated nuclear antigen (LANA) and glycoprotein (K8.1) and calculated case-control-adjusted odds ratios (ORadj ) and 95% confidence intervals (CI) in relation to KS and KSHV infection, before (1995-2004), early (2005-2009) and late (2010-2016) ART rollout periods. KSHV seropositivity among 1237 KS cases was 98%. Among 6649 controls, KSHV seropositivity was higher in males (ORadj =1.4 [95%CI 1.23-1.52]), in persons with HIV, (ORadj =4.2 [95%CI 3.74-4.73]) and lower in high school leavers (ORadj =0.7 [95%CI 0.59-0.83]). KSHV seropositivity declined over the three ART rollout periods (37%, 28% and 28%, Ptrend < .001) coinciding with increases in high school leavers over the same periods (46%, 58% and 67%, Ptrend < .001). HIV-1 seroprevalence increased from 10% in the pre-ART period to 22% in the late ART period (Ptrend < .001). Compared to HIV-1 and KSHV seronegatives, KSHV seropositives yielded an OR for KS of 26 (95%CI 11-62) in HIV-1 seronegative participants and an OR of 2501 (95%CI 1083-5776) in HIV-1 seropositive participants. HIV-1 increases the risk of KS in those infected with KSHV by 100-fold. Declines in KSHV seroprevalence coincide with ART rollout and with improvements in educational standards and general hygiene.

Cytomegalovirus retinitis in hospitalized people living with HIV in the late antiretroviral therapy era in São Paulo, Brazil.

There is scarce information on AIDS-related cytomegalovirus (CMV) retinitis in middle-income countries. The objectives of this study were to identify the prevalence of active CMV retinitis in severely immunosuppressed people living with HIV (PLWHIV) and to describe its main features. This retrospective cohort study was carried out at a tertiary center in São Paulo, Brazil. We included hospitalized adults PLWHIV with CD4 count ≤100 cells/μL, ≥ one quantitation of CMV DNA in plasma, and indirect ophthalmoscopy evaluation. Thirty-eight (21.6%) of 176 participants had at least an ophthalmoscopy diagnosis and only 3 (1.7%) individuals presented active CMV retinitis. All these participants were male, and retinitis was asymptomatic in 2 cases. Two participants had extraocular end-organ CMV disease and detectable CMV DNA in plasma. These results show a low prevalence of active CMV retinitis in the evaluated population. However, 2 of 3 participants had asymptomatic active CMV retinitis and a fifth of participants had at least one ophthalmoscopy diagnosis, suggesting the need for routine ophthalmologic evaluation in hospitalized severely immunosuppressed PLWHIV. The profile of participants with active CMV retinitis was similar to that described in the pre-ART era and quantitation of CMV DNA in plasma was variable.

AIDS-related cytomegalovirus encephalitis in the late ART era: A retrospective cohort study at a referral center in Brazil.

AIDS-related cytomegalovirus (CMV) encephalitis has declined in the combined antiretroviral therapy (ART) era in high-income countries. However, there is scarce information on CMV encephalitis in low- and middle-income countries. The objectives of this study were to identify the prevalence of AIDS-related CMV encephalitis and describe its main features. This was a retrospective cohort study carried out at a referral center in São Paulo, Brazil. We included adult people living with HIV/AIDS (PLWHA), hospitalized in 2019, with a CD4 cell count ≤100/mm3 and quantitation CMV DNA results in plasma. Cases with compatible neurological manifestations and detection of CMV DNA by polymerase chain reaction (PCR) in cerebrospinal fluid samples were defined as CMV encephalitis. Among 761 PLWHA hospitalized, 248 (32.5%) cases were included in this study. Prevalence of CMV encephalitis was 2.4% (6/248) among all included cases and 7.7% (6/78) among individuals with neurological opportunistic diseases. The six patients with CMV encephalitis were males and had CD4 cell count <50/mm3. Five (83%) cases had CMV encephalitis as AIDS-defining disease and showed CMV DNA detection by PCR >50,000UI/mL plasma. All six cases received anti-CMV therapy (ganciclovir, n = 4; ganciclovir plus foscarnet, n = 2) and five were discharged to home. CMV encephalitis was not uncommon among hospitalized PLWHA with neurological opportunistic diseases. The epidemiological and immunological profile of individuals with CMV encephalitis was similar to that described in the pre-ART era, but in contrast, most cases were treated and discharged from the hospital.

Treatment Outcomes of HIV Infected Children After Initiation of Antiretroviral Therapy in Southwest China: An Observational Cohort Study.

BackgroundThe number of HIV infected children receiving antiviral treatment in Guangxi is increasing. Understanding factors and trends of mortality and attrition in HIV-infected children under antiretroviral therapy (ART) was an urgent need to improve treatment outcomes. This study aimed to estimate mortality and attrition rates and identify factors that were associated with mortality and attrition after ART initiation among children with HIV in Guangxi, China between 2004 and 2018.MethodsCohort study data were extracted from the National Free Antiretroviral Treatment Program (NFATP) database, which has standard guidelines for core treatment indicators and other data at all HIV/AIDS treatment facilities in Guangxi. A total of 901 HIV-infected children who have started ART were included in the study. The study collected the following data: age, gender, WHO clinic stages before ART, CD4 cell count before ART, Cotrimoxazole prophylaxis (CTX) use before ART, initial ART regimen, malnutrition before ART, abnormal liver function before ART, abnormal kidney function before ART, severe anemia before ART, and the time lag between an HIV diagnosis and ART initiation.ResultsHIV-infected children under ART had a mortality rate of 0.87 per 100 person-years [95% Confidence Interval (CI) 0.63–1.11], and an attrition rate of 3.02 per 100 person-years (95% CI 2.57–3.47). Mortality was lower among children with a CD4 count between 200 and 500 copies/ml [Adjusted Hazard Ratio (AHR) 0.22, 95% CI 0.09–0.55], and CD4 count ≥500 copies/ml (AHR 0.10, 95% CI 0.03–0.29); but higher among children with late ART initiation at 1–3 months (AHR 2.30, 95% CI 1.07–4.94), and at ≥3 months (AHR 2.22, 95% CI 1.04–4.74). Attrition was lower among children with a CD4 count ≥500 copies/ml (AHR 0.62, 95% CI 0.41–0.95), but higher among children with late ART initiation at 1–3 months (AHR 1.55, 95% CI 1.05–2.30).ConclusionSupportive programs are needed to educate children's families and parents on early ART, link HIV-infected children to care and retain them in care among other programs that treat and manage the medical conditions of HIV-infected children before ART initiation.

Effect of Late Testing and Antiretroviral Treatment on Mortality Among People Living With HIV in the Era of Treat-All in Guangdong Province, China, 1992-2018: A Cohort Study.

Late testing and antiretroviral therapy (ART) prevailed among people living with HIV (PLHIV) and impacted the benefit of immediate ART. This study aimed to identify the benefit of the test-and-immediate-treat policy in China, the effect of immediate ART, and the influence of late testing and ART on the whole PLHIV in Guangdong Province, China. We designed two tendency analyses in aggregative form and two cohorts (surveillance and ART cohort) in individuals' perspectives based on the HIV/AIDS Comprehensive Response Information Management System. Two interrupted time series models were conducted for tendency analysis from 2009 to 2018 to explore the all-cause and short-term mortality decrease after the test-and-immediate-treat policy. A time-dependent Cox model was performed for the surveillance cohort from 1992 to 2018 and a joint model was utilized for the ART cohort to identify the effect of immediate ART and the influence of late testing and ART on death. The tendency analysis included 324,914 and 68,679 person-year for all-cause/short-term mortality. A total of 49,289 and 26,287 PLHIV were recruited in the surveillance and ART cohort with 5,557 and 459 deaths, respectively. The short-term mortality dropped from 4.69 cases/100 person-year in January 2009 to 0.35 cases/100 person-year in December 2018 (standardized rate). The all-cause mortality saw a decreasing trend from 1.46 cases/100 person-year in January 2009 to 0.14 cases/100 person-year in December 2018 (standardized rate). The tendency analysis showed a significant short-term mortality slope decrease after the test-and-immediate-treat policy (P = 0.024). From the surveillance cohort, late testing, in general, was a risk factor for all-cause mortality [hazard ratio (HR) = 1.330, 95% CI, 1.250, 1.416]. ART cohort showed higher hazards of all-cause mortality among PLHIV with no late testing, but late ART (HR = 1.690, 95% CI, 1.166, 2.451) and both the late testing and late ART (HR = 1.335, 95% CI, 1.042, 1.710). Immediate ART might decrease the hazard of all-cause death though it is insignificant (HR = 0.923, 95% CI: 0.755, 1.129) in the ART cohort. The test-and-immediate-test policy brought benefit to PLHIV. We should enlarge HIV testing using comprehensive approaches to decrease late testing and ART and increase the benefit of immediate ART.

Factors Associated With Late Antiretroviral Therapy Initiation Among People Living With HIV in Southern Iran: A Historical Cohort Study.

ObjectivesLate initiation of antiretroviral therapy (ART) is associated with poor outcome among people living with HIV (PLHIV) and higher risk of transmission of infection. This study was conducted to identify the determinants of late ART initiation among PLHIV in Southern Iran.MethodsA historical cohort study was conducted on 1,326 PLHIV of ≥15 years of age who were registered with the behavioral diseases counseling center (BDCC) in southern Iran from August 1997 to March 2021. Late ART initiation was defined as a CD4 cell count <200 cells/mm3 or having a clinical AIDS diagnosis at the time of ART initiation. The required demographic and clinical data were collected from the patients' medical records. Multiple regression analysis was conducted to define late ART initiation associated factors.ResultsLate ART initiation was found among 81.9% of patients. Based on the results of the multivariate analysis, older age (odds ratio [OR] = 1.02, 95% CI = 1.00–1.04), being single (ORsingle/married = 1.80, 95% CI = 1.17–2.78), history of drug use (ORyes/no = 1.64, 95% CI = 1.02–2.62), year of ART initiation (OR2011−2013/2018−2021 = 3.65, 95% CI = 2.28–5.86), and possible route of transmission (ORdruginjection/sexual = 7.34, 95% CI = 1.16–46.21) were directly associated with the risk of late ART initiation.ConclusionsThe results show that the prevalence of late ART initiation was alarmingly high. For better infection control and better prognosis of infection, people at high risk need to be provided with timely services (e.g., diagnosis, treatment, training, and social support).

COVID-19 Clinical Presentation Among HIV-Infected Persons in China: A Systematic Review.

Purpose of ReviewThe impact of HIV infection on the natural history of COVID-19 is unknown, given the recency of the human spread of SARS-CoV-2 (CoV). We reviewed published case series/reports of CoV-HIV coinfections to clarify epidemiologic and clinical features in China, the first nation with pandemic experience.Recent FindingsAssuming that HIV-infected persons were at average risk of CoV infection in Wuhan, we estimated HIV-CoV coinfected persons to number 412 (95%CI: 381-442); our review encompassed an estimated 16.7% (69/412) of Wuhan. Men (many of whom reported sex with other men) accounted for 71.1% (54/76) of the cases reported in China. The median age was 48.0 years old (range 24-77, interquartile:37-57). The median CD4+ cell count at the last clinical visit was 421 cells/μL; 83.0% had an undetectable viral load. Among 31 patients with clinical details reported, fatigue (41.9%), respiratory distress (41.9%), and gastrointestinal symptoms (26.7%) were most common. Among the 52 cases reporting COVID-19 clinical severity, 46.2% were severe, 44.2% mild, and 9.6% asymptomatic COVID-19. Late antiretroviral therapy (ART) was reported by 30.4% (7/23) among whom 57.1% (4/7) were confirmed as severe COVID-19. The case fatality rate was 9.1% (3/33). Severe disease and death were less common among persons who took ART prior to the COVID-19 diagnosis. Of 16 reported IL-6 results, 68.7% were within the normal range.SummaryEarlier use of ART was associated with a better COVID-19 prognosis with CoV-HIV co-infection reported from China through early 2021, but small sample sizes limit definitive conclusions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11904-022-00606-0.

Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis.

IntroductionAdolescents living with HIV are subject to multiple co‐morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project.MethodsData were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10–17 years, were included. Growth was measured using height‐for‐age Z‐scores (HAZ, stunting if <‐2 SD, WHO growth charts). Linear mixed‐effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex‐specific models with fractional polynomials were used to model non‐linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age.ResultsA total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two‐thirds lived in East and Southern Africa, and median age at ART initiation ranged from <3 years in North America and Europe to >7 years in sub‐Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia‐Pacific; 19% overall had CD4 counts <500 cells/mm3. Across adolescence, higher HAZ was observed in females and among those in high‐income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch‐up with non‐stunted, early ART‐treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3. This decline was observed across all regions, in males and females.ConclusionsGrowth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood.

The Impact of Timing of Antiretroviral Therapy Initiation on Retention in Care, Viral Load Suppression and Mortality in People Living with HIV: A Study in a University Hospital in Thailand.

Studies investigating same-day antiretroviral therapy (ART) initiation demonstrate different clinical outcomes depending on settings. We retrospectively reviewed adults with newly positive human immunodeficiency virus (HIV) antibody testing. The proportion of individuals who were retained in care at 12 months was compared between early (≤2 weeks) and late (>2 weeks) ART initiation groups. Of all, the median (IQR) time from HIV diagnosis to ART initiation was 18 (9-30) days. This duration was 7 (7-13) days in the early ART initiation group (n = 116) and 28 (21-46) days in the late ART initiation group (n = 154). In the multivariate logistic regression, having pneumocystis pneumonia [odds ratio (OR) 9.30, 95% CI 2.56-33.75], tuberculosis (OR 2.21, 95% CI 1.03-4.73), and weight loss (OR 12.98, 95% CI 1.00-167.68) were associated with late ART initiation. The early ART initiation group had a slightly higher proportion of individuals retained in care at 12 months than those in the late ART initiation group (88.8% vs 80.5%, P = .066) and had a higher significant proportion of HIV viral load suppression (81.0% vs 70.1%, P = .041). No significant differences were observed in the proportion of individuals who died at 12 months (2.6% vs 3.2%, P = 1.000) between the two groups. Early ART initiation trends to retain individuals in care and higher HIV viral load suppression was determined. Nevertheless, ART initiation timing might not be a solely important factor in improving HIV care and minimizing mortality among HIV-infected individuals in a university hospital setting.

Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells

People living with HIV (PLWH) are at increased risk for developing skin and mucosal malignancies despite systemic reconstitution of CD4+ Tcells upon antiretroviral therapy (ART). The underlying mechanism of chronic tissue-related immunodeficiency in HIV is unclear. We found that skin CD4+ tissue-resident memory T (Trm) cells were depleted after HIV infection and replenished only upon early ART initiation. TCR clonal analysis following early ART suggested a systemic origin for reconstituting CD4+ Trm cells. Single-cell RNA sequencing in PLWH that received late ART treatment revealed a loss of CXCR3+ Trm cells and a tolerogenic skin immune environment. Human papilloma virus-induced precancerous lesion biopsies showed reduced CXCR3+ Trm cell frequencies in the mucosa in PLWH versus HIV- individuals. These results reveal an irreversible loss of CXCR3+ Trm cells confined to skin and mucosa in PLWH who received late ART treatment, which may be a precipitating factor in the development of HPV-related cancer.

Size of HIV-1 reservoir is associated with telomere shortening and immunosenescence in early-treated European children with perinatally acquired HIV-1.

IntroductionPersistence of HIV‐1, causing chronic immune activation, is a key determinant of premature senescence. Early antiretroviral therapy (ART) has been associated with a reduced HIV‐1 reservoir in children with perinatally acquired HIV‐1 (PHIV), but its impact on the senescence process is an open question. We investigated the association between HIV‐1 reservoir and biological and immune ageing profile in PHIV enrolled in the multicentre cross‐sectional study CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART) conducted within the EPIICAL (Early treated Perinatally HIV Infected individuals: Improving Children's Actual Life) consortium.MethodsBetween September 2017 and June 2018, CARMA enrolled 40 PHIV who started ART before 2 years of age and had undetectable viremia for at least 5 years before sampling date. Samples from 37 children with a median age of 13.8 years were available for this study. HIV‐1 DNA copies on CD4 cells, relative telomere length (marker of cellular senescence) and levels of T‐cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Immunological profile was assessed by flow cytometry. Associations between molecular and phenotypic markers, HIV‐1 reservoir and age at ART initiation were explored using a multivariable Poisson regression.ResultsHigher HIV‐1 reservoir was associated (p<0.001) with telomere shortening (incidence rate ratio [IRR] = 0.15 [0.13–0.17]), immunosenescence (CD28–CD57+, IRR = 1.23 [1.21–1.26]) and immunoactivation (CD38+ HLADR+, IRR = 7.29 [6.58–8.09]) of CD4 cells. Late ART initiation (after 6 months of age) correlated with higher HIV‐1 reservoir levels (552 [303–1001] vs. 89 [56–365] copies/106 CD4 cells, p = 0.003) and percentage of CD4 senescent cells (2.89 [1.95–6.31] vs. 1.02 [0.45–2.69, p = 0.047). TREC levels in CD8 cells were inversely associated with HIV‐1 reservoir (IRR = 0.77 [0.76–0.79]) and were significantly lower in late treated PHIV (1128 [486–1671] vs. 2278 [1425–3314], p = 0.042).ConclusionsLater ART initiation is associated with higher HIV‐1 reservoir size, which correlates with increased telomere shortening and senescence of CD4 cells. Timing of ART initiation in infancy has long‐term consequences on the immune and biological ageing profile of children with perinatally acquired HIV‐1.

Patterns of engagement in HIV care during pregnancy and breastfeeding: findings from a cohort study in North-Eastern South Africa

BackgroundEliminating mother-to-child transmission of HIV (MTCT) in sub-Saharan Africa is hindered by limited understanding of HIV-testing and HIV-care engagement among pregnant and breastfeeding women.MethodsWe investigated HIV-testing and HIV-care engagement during pregnancy and breastfeeding from 2014 to 2018 in the Agincourt Health and Demographic Surveillance System (HDSS). We linked HIV patient clinic records to HDSS pregnancy data. We modelled time to a first recorded HIV-diagnosis following conception, and time to antiretroviral therapy (ART) initiation following diagnosis using Kaplan-Meier methods.We performed sequence and cluster analyses for all pregnancies linked to HIV-related clinic data to categorise MTCT risk period engagement patterns and identified factors associated with different engagement patterns using logistic regression.We determined factors associated with ART resumption for women who were lost to follow-up (LTFU) using Cox regression.ResultsSince 2014, 15% of 10,735 pregnancies were recorded as occurring to previously (51%) or newly (49%) HIV-diagnosed women. New diagnoses increased until 2016 and then declined. We identified four MTCT risk period engagement patterns (i) early ART/stable care (51.9%), (ii) early ART/unstable care (34.1%), (iii) late ART initiators (7.6%), and (iv) postnatal seroconversion/early, stable ART (6.4%). Year of delivery, mother’s age, marital status, and baseline CD4 were associated with these patterns. A new pregnancy increased the likelihood of treatment resumption following LTFU.ConclusionAlmost half of all pregnant women did not have optimal ART coverage during the MTCT risk period. Programmes need to focus on improving retention, and leveraging new pregnancies to re-engage HIV-positive women on ART.

Effect of antiretroviral therapy initiation time and baseline CD4+ cell counts on AIDS-related mortality among former plasma donors in China: a 21-year retrospective cohort study

ABSTRACT Background The conventional survival analysis model on HIV/AIDS prognosis is the Cox proportional hazard model, which deals with only one event type, death, regardless of the cause. Few studies have used a competing risk model to evaluate the predictors of AIDS-related mortality. Objective To estimate the influence of antiretroviral therapy (ART) initiation time and baseline CD4+ cell counts on acquired immunodeficiency syndrome (AIDS)-related death among former plasma donors. Methods A retrospective cohort study was conducted involving 11,905 human immunodeficiency virus (HIV) or AIDS patients in a high-risk area of Henan province in China between 1995 and 2016. Demographic and clinical data were collected. Sub-distribution hazard ratios (sHRs) for AIDS-related mortality with baseline CD4+ cell counts and ART initiation time were determined using a competing risk model. Results Patients who initiated ART within 90 days of HIV/AIDS diagnosis (sHR: 0.24, 95% CI: 0.22–0.27) or had baseline CD4+ counts of >500 cells/μL (sHR: 0.23, 95% CI: 0.19–0.28) were associated with lower AIDS-related mortality risk. Patients with ART initiation time >1 year but CD4+ counts >350 cells/μL (sHR: 4.42, 95% CI: 3.30–5.91) had a higher AIDS-related mortality risk than those with ART initiation time >90 days but CD4+ counts ≤350 cells/μL (sHR: 4.33, 95% CI: 3.58–5.23). Conclusions Our results demonstrate that patients with high CD4+ cell counts and late ART had a 9% higher risk of AIDS-related death than those with low CD4+ cell counts and early ART. This study confirms the great significance of immediate ART initiation among former plasma donor HIV patients in China.

Alcohol use and viral suppression in HIV-positive Kenyan female sex workers on antiretroviral therapy

BackgroundExcessive alcohol intake has been associated with poor adherence to antiretroviral therapy (ART). The impact of alcohol on viral suppression is particularly important among groups at high risk of HIV transmission, such as female sex workers (FSWs). Few studies have directly evaluated the association between alcohol use and HIV viral load. We hypothesized that hazardous or harmful alcohol use is associated with detectable plasma viral load among HIV-positive FSWs.MethodsA prospective cohort study was conducted among HIV-positive FSWs in Mombasa, Kenya. Hazardous or harmful alcohol use was assessed yearly and defined as an Alcohol Use Disorders Identification Test (AUDIT) score ≥7. Detectable viral load was assessed every six months and defined as ≥180 c/mL. Adherence measures were collected monthly and included late ART refill (>48 hours) and self-reported adherence, using both a validated self-rating scale of ability to take medication and visual analog scale (VAS) of ART use in the last month. Generalized estimating equations were used to estimate adjusted relative risks (aRR) and 95% confidence intervals (CI).ResultsThis analysis included 366 participants followed monthly between October 2012 and March 2018. At baseline, AUDIT scores indicated hazardous alcohol use (AUDIT 7–15) in 14.3%, harmful alcohol use (AUDIT 16–19) in 1.4%, and alcohol dependency (AUDIT ≥20) in 1.4% of participants. After adjusting for potential confounders, a combined exposure including hazardous, harmful, and dependent alcohol use was not associated with detectable viral load (aRR 1.10, 95%CI 0.63–1.92) or late ART refill (aRR 1.13, 95%CI 0.82–1.56), but was associated with lower self-rated ability to take medication (aRR 2.38, 95%CI 1.42–3.99) and a lower rate of self-reported perfect ART adherence by VAS (aRR 2.62, 95%CI 1.84–3.71).ConclusionsIn this FSW cohort, while participants reporting hazardous, harmful, or dependent alcohol use were not more likely to have a detectable viral load, they were more likely to report lower ART adherence. These results suggest that interventions targeting alcohol use among this population of FSWs may not have a large impact on viral suppression.