Loss to follow‐up among children and adolescents growing up with HIV infection: age really matters

Introduction : Globally, increasing numbers of HIV‐infected children are reaching adolescence due to antiretroviral therapy (ART). We investigated rates of loss‐to‐follow‐up (LTFU) from HIV care services among children as they transition from childhood through adolescence. Methods : Individuals aged 5–19 years initiated on ART in a public‐sector HIV clinic in Bulawayo, Zimbabwe, between 2005 and 2009 were included in a retrospective cohort study. Participants were categorized into narrow age‐bands namely: 5–9 (children), 10–14 (young adolescents) and 15–19 (older adolescents). The effect of age at ART initiation, current age (using a time‐updated Lexis expansion) and transitioning from one age group to the next on LTFU was estimated using Poisson regression. Results : Of 2273 participants, 1013, 875 and 385 initiated ART aged 5–9, 10–14 and 15–19 years, respectively. Unlike those starting ART as children, individuals starting ART as young adolescents had higher LTFU rates after moving to the older adolescent age‐band (Adjusted rate ratio (ARR) 1.54; 95% CI: 0.94–2.55) and similarly, older adolescents had higher LTFU rates after transitioning to being young adults (ARR 1.79; 95% CI: 1.05–3.07). In older adolescents, the LTFU rate among those who started ART in that age‐band was higher compared to the rate among those starting ART at a younger age (ARR = 1.70; 95% CI: 1.05, 2.77). This however did not hold true for other age‐groups. Conclusions : Adolescents had higher rates of LTFU compared to other age‐groups, with older adolescents at particularly high risk in all analyses. Age‐updated analyses that examine movement across narrow age‐bands are paramount in understanding how developmental heterogeneity in children affects HIV outcomes.     

Virological response and resistances over 12 months among HIV‐infected children less than two years receiving first‐line lopinavir/ritonavir‐based antiretroviral therapy in Cote d’Ivoire and Burkina Faso: the MONOD ANRS 12206 cohort

Introduction : Lopinavir/ritonavir‐based antiretroviral therapy (ART) is recommended for all HIV‐infected children less than three years. However, little is known about its field implementation and effectiveness in West Africa. We assessed the 12‐month response to lopinavir/ritonavir‐based antiretroviral therapy in a cohort of West African children treated before the age of two years. Methods : HIV‐1‐infected, ART‐naive except for a prevention of mother‐to‐child transmission (PMTCT), tuberculosis‐free, and less than two years of age children with parent's consent were enrolled in a 12‐month prospective therapeutic cohort with lopinavir/ritonavir ART and cotrimoxazole prophylaxis in Ouagadougou and Abidjan. Virological suppression (VS) at 12 months (viral load [VL] <500 copies/mL) and its correlates were assessed. Result s : Between May 2011 and January 2013, 156 children initiated ART at a median age of 13.9 months (interquartile range: 7.8–18.4); 63% were from Abidjan; 53% were girls; 37% were not exposed to any PMTCT intervention or maternal ART; mother was the main caregiver in 81%; 61% were classified World Health Organization Stage 3 to 4. After 12 months on ART, 11 children had died (7%), 5 were lost‐to‐follow‐up/withdrew (3%), and VS was achieved in 109: 70% of children enrolled and 78% of those followed‐up. When adjusting for country and gender, the access to tap water at home versus none (adjusted odds ratio (aOR): 2.75, 95% confidence interval (CI): 1.09–6.94), the mother as the main caregiver versus the father (aOR: 2.82, 95% CI: 1.03–7.71), and the increase of CD4 percentage greater than 10% between inclusion and 6 months versus <10% (aOR: 2.55, 95% CI: 1.05–6.18) were significantly associated with a higher rate of VS. At 12 months, 28 out of 29 children with VL ≥1000 copies/mL had a resistance genotype test: 21 (75%) had ≥1 antiretroviral (ARV) resistance (61% to lamivudine, 29% to efavirenz, and 4% to zidovudine and lopinavir/ritonavir), of which 11 (52%) existed before ART initiation. Conclusions : Twelve‐month VS rate on lopinavir/ritonavir‐based ART was high, comparable to those in Africa or high‐income countries. The father as the main child caregiver and lack of access to tap water are risk factors for viral failure and justify a special caution to improve adherence in these easy‐to‐identify situations before ART initiation. Public health challenges remain to optimize outcomes in children with earlier ART initiation in West Africa.     

Postnatal HIV transmission in breastfed infants of HIV‐infected women on ART: a systematic review and meta‐analysis

Introduction : To systematically review the literature on mother‐to‐child transmission in breastfed infants whose mothers received antiretroviral therapy and support the process of updating the World Health Organization infant feeding guidelines in the context of HIV and ART. Methods : We reviewed experimental and observational studies; exposure was maternal HIV antiretroviral therapy (and duration) and infant feeding modality; outcomes were overall and postnatal HIV transmission rates in the infant at 6, 9, 12 and 18 months. English literature from 2005 to 2015 was systematically searched in multiple electronic databases. Papers were analysed by narrative synthesis; data were pooled in random effects meta‐analyses. Postnatal transmission was assessed from four to six weeks of life. Study quality was assessed using a modified Newcastle‐Ottawa Scale (NOS) and GRADE. Results and discussion : Eleven studies were identified, from 1439 citations and review of 72 abstracts. Heterogeneity in study methodology and pooled estimates was considerable. Overall pooled transmission rates at 6 months for breastfed infants with mothers on antiretroviral treatment (ART) was 3.54% (95% CI: 1.15–5.93%) and at 12 months 4.23% (95% CI: 2.97–5.49%). Postnatal transmission rates were 1.08 (95% CI: 0.32–1.85) at six and 2.93 (95% CI: 0.68–5.18) at 12 months. ART was mostly provided for PMTCT only and did not continue beyond six months postpartum. No study provided data on mixed feeding and transmission risk. Conclusions : There is evidence of substantially reduced postnatal HIV transmission risk under the cover of maternal ART. However, transmission risk increased once PMTCT ART stopped at six months, which supports the current World Health Organization recommendations of life‐long ART for all.     

High self‐reported non‐adherence to antiretroviral therapy amongst adolescents living with HIV in Malawi: barriers and associated factors

Introduction : Globally adolescents and young adults account for more than 40% of new HIV infections, and HIV‐related deaths amongst adolescents increased by 50% from 2005 to 2012. Adherence to antiretroviral therapy (ART) is critical to control viral replication and preserve health; however, there is a paucity of research on adherence amongst the growing population of adolescents living with HIV/AIDS (ALHIV) in Southern Africa. We examined levels of self‐reported ART adherence, barriers to adherence, and factors associated with non‐adherence amongst ALHIV in Malawi. Methods : Cross‐sectional study of 519 ALHIV (12–18 years) attending two large HIV clinics in central and south‐eastern Malawi. Participants self‐reported missed doses (past week/month), barriers to adherence, and completed questionnaires on past traumatic events/stressors, disclosure, depression, substance use, treatment self‐efficacy, and social support. Biomedical data were retrieved from existing medical records. Multivariate logistic regression was performed to identify factors independently associated with self‐reported ART adherence (7 day recall). Results : The mean age of participants (SD) was 14.5 (2) years and 290 (56%) were female. Of the 519 participants, 153 (30%) reported having missed ART doses within the past week, and 234 (45%) in the past month. Commonly reported barriers to adherence included forgetting (39%), travel from home (14%), busy with other things (11%), feeling depressed/overwhelmed (6%), feeling stigmatized by people outside (5%) and within the home (3%). Factors found to be independently associated with missing a dose in the past week were drinking alcohol in the past month (OR 4.96, 95% CI [1.41–17.4]), missed clinic appointment in the past 6 months (OR 2.23, 95% CI [1.43–3.49]), witnessed or experienced violence in the home (OR 1.86, 95% CI [1.08–3.21]), and poor treatment self‐efficacy (OR 1.55 95% CI [1.02–2.34]). Sex and age were not associated with adherence. Conclusions : In our study, nearly half of all ALHIV reported non‐adherence to ART in the past month. Violence in the home or alcohol use in the past year as well as poor treatment self‐efficacy were associated with worse adherence. Sub‐optimal adherence is a major issue for ALHIV and compromise treatment outcomes. Programmes specifically tailored to address those challenges most pertinent to ALHIV may help improve adherence to ART.     

Multicentre analysis of second‐line antiretroviral treatment in HIV‐infected children: adolescents at high risk of failure

Introduction : The number of HIV‐infected children and adolescents requiring second‐line antiretroviral treatment (ART) is increasing in low‐ and middle‐income countries (LMIC). However, the effectiveness of paediatric second‐line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second‐line ART outcomes for children and assessed the need for paediatric third‐line ART. Methods : We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second‐line ART in LMIC, contacting the corresponding study groups and including patient‐level data on virologic and clinical outcomes. Kaplan–Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second‐line treatment. Results : We included 12 cohorts representing 928 children on second‐line protease inhibitor (PI)‐based ART in 14 countries in Asia and sub‐Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9–19.4) of children experienced virologic failure. Adolescents (10–18 years) had failure rates of 14.5 (95% CI 11.9–17.6) per 100 person‐years compared to 4.5 (95% CI 3.4–5.8) for younger children (3–9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first‐line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24–48 months and >48 months, respectively, compared to <24 months). Conclusions : In LMIC, paediatric PI‐based second‐line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI‐based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.     

Human immunodeficiency virus care cascade among sub‐populations in Rakai,Uganda: an observational study

Introduction : To assess progress towards the UNAIDS 90–90–90 initiative targets, we examined the HIV care cascade in the population‐based Rakai Community Cohort Study (RCCS) in rural Uganda and examined differences between sub‐groups. Methods : Self‐reports and clinical records were used to assess the proportion achieving each stage in the cascade. Statistical inference based on a χ² test for categorical variables and modified Poisson regression were used to estimate prevalence risk ratios (PRRs) and 95% confidence intervals (CI) for enrolment into care and initiating antiretroviral therapy (ART). Results : From September 2013 through December 2015, 3,666 HIV‐positive participants were identified in the RCCS. As of December 2015, 98% had received HIV Counseling and Testing (HCT), 74% were enrolled in HIV care, and 63% had initiated ART of whom 92% were virally suppressed after 12 months on ART. Engagement in care was lower among men than women (enrolment in care: adjPRR 0.84, 95% CI 0.77–0.91; ART initiation: adjPRR 0.75, 95% CI 0.69–0.82), persons aged 15–24 compared to those aged 30–39 (enrolment: adjPRR 0.72, 95% CI 0.63–0.82; ART: adjPRR 0.69, 95%CI 0.60–0.80), unmarried persons (enrolment: adjPRR 0.84, 95% CI 0.71–0.99; ART adjPRR 0.80, 95% CI 0.66–0.95), and new in‐migrants (enrolment: adjPRR 0.75, 95% CI 0.67–0.83; ART: adjPRR 0.76, 95% CI 0.67–0.85). This cohort achieved 98–65–92 towards the UNAIDS “90–90–90” targets with an estimated 58% of the entire HIV‐positive RCCS population virally suppressed. Conclusions : This cohort achieved over 90% in both HCT and viral suppression among ART users, but only 65% in initiating ART, likely due to both an ART eligibility criterion of <500 CD4 cells/mL and suboptimal entry into care among men, younger individuals, and in‐migrants. Interventions are needed to promote enrolment in HIV care, particular for hard‐to‐reach sub‐populations.     

Factors associated with retention in Option B+ in Malawi: a case control study

Introduction : There are limited data on factors associated with retention in Option B+. We sought to explore the characteristics of women retained in Option B+ in Malawi, with a focus on the role of HIV disclosure, awareness of partner HIV status, and knowledge around the importance of Option B+ for maternal–child health. Methods : We performed a case‐control study of HIV‐infected women in Malawi initiated on antiretroviral therapy (ART) under Option B+. Cases were enrolled if they met criteria for default from Option B+ (out of ART for >60 days), and controls were enrolled in approximately 3:1 ratio if they were retained in care for at least 12 months. We surveyed socio‐demographic characteristics, HIV disclosure and awareness of partner HIV status, self‐report about receiving pre‐ART education, and knowledge of Option B+. Univariate logistic regression was performed to determine factors associated with retention. Multivariate logistic regression model was used to evaluate the relationship between HIV disclosure, Option B+ knowledge, and retention after adjusting for age, schooling, and travel time to clinic. Results : We enrolled 50 cases and 153 controls. Median age was 30 years (interquartile range (IQR) 25–34), and the majority (82%) initiated ART during pregnancy at a median gestational age of 24 weeks (IQR 16–28). Ninety‐one per cent of the cases (39/43) who started ART during pregnancy defaulted by three months postpartum. HIV disclosure to the primary sex partner was more common among women retained in care (100% versus 78%, p < 0.001). Odds of retention were significantly higher among women with: age >25 years (odds ratio (OR) 2.44), completion of primary school (OR 3.06), awareness of partner HIV status (OR 5.20), pre‐ART education (OR 6.17), higher number of correct answers to Option B+ knowledge questions (OR 1.82), and support while taking ART (OR 3.65). Pre‐ART education and knowledge were significantly correlated (r = 0.43, p < 0.001). In multivariate analysis, awareness of partner HIV status (OR 4.07, 95% confidence interval (CI) 1.51–10.94, p = 0.02) and Option B+ knowledge (OR 1.60, 95% CI 1.15–2.23, p = 0.004) remained associated with retention. Conclusions : Interventions that address partner disclosure and strengthen pre‐ART education around the benefits of ART for maternal and child health should be evaluated to improve retention in Malawi's Option B+ programme.     

Twelve‐year mortality in adults initiating antiretroviral therapy in South Africa

Introduction : South Africa has the largest number of individuals living with HIV and the largest antiretroviral therapy (ART) programme worldwide. In September 2016, ART eligibility was extended to all 7.1 million HIV‐positive South Africans. To ensure that further expansion of services does not compromise quality of care, long‐term outcomes must be monitored. Few studies have reported long‐term mortality in resource‐constrained settings, where mortality ascertainment is challenging. Combining site records with data linked to the national vital registration system, sites in the International Epidemiology Databases to Evaluate AIDS Southern Africa collaboration can identify >95% of deaths in patients with civil identification numbers (IDs). This study used linked data to explore long‐term mortality and viral suppression among adults starting ART in South Africa. Methods : The study was a cohort analysis of routine data on adults with IDs starting ART 2004–2015 in five large ART cohorts. Mortality was estimated overall and by gender using the Kaplan‐Meier estimator and Cox's proportional hazards regression. Standardized mortality ratios (SMRs) were calculated by dividing observed numbers of deaths by numbers expected if patients had been HIV‐negative. Viral suppression in patients with viral loads (VLs) in their last year of follow‐up was the secondary outcome. Results : Among 72,812 adults followed for 350,376 person years (pyrs), the crude mortality rate was 3.08 (95% CI 3.02–3.14)/100 pyrs. Patients were predominantly female (67%) and the percentage of men initiating ART did not increase. Cumulative mortality 12 years after ART initiation was 23.9% (33.4% male and 19.4% female). Mortality peaked in patients enrolling in 2007–2009 and was higher in men than women at all durations. Observed mortality rates were higher than HIV‐negative mortality, decreasing with duration. By 48 months, observed mortality was close to that in the HIV‐negative population, and SMRs were similar for all baseline CD4 strata. Three‐quarters of patients had VLs in their last year, and 86% of these were virally suppressed. Conclusions : The South African ART programme has shown a remarkable ability to initiate and manage patients successfully over 12 years, despite rapid expansion. With further scale‐up, testing and initiating men on ART must be a national priority.     

When patients fail UNAIDS’ last 90 ‐ the “failure cascade” beyond 90‐90‐90 in rural Lesotho,Southern Africa: a prospective cohort study

Introduction : HIV‐infected individuals on first‐line antiretroviral therapy (ART) in resource‐limited settings who do not achieve the last “90” (viral suppression) enter a complex care cascade: enhanced adherence counselling (EAC), repetition of viral load (VL) and switch to second‐line ART aiming to achieve resuppression. This study describes the “failure cascade” in patients in Lesotho. Methods : Patients aged ≥16 years on first‐line ART at 10 facilities in rural Lesotho received a first‐time VL in June 2014. Those with VL ≥80 copies/mL were included in a cohort. The care cascade was assessed at four points: attendance of EAC, result of follow‐up VL after EAC, switch to second‐line in case of sustained unsuppressed VL and outcome 18 months after the initial unsuppressed VL. Multivariate logistic regression was used to assess predictors of being retained in care with viral resuppression at follow‐up. Results : Out of 1563 patients who underwent first‐time VL, 138 (8.8%) had unsuppressed VL in June 2014. Out of these, 124 (90%) attended EAC and 116 (84%) had follow‐up VL (4 died, 2 transferred out, 11 lost, 5 switched to second‐line before follow‐up VL). Among the 116 with follow‐up VL, 36 (31%) achieved resuppression. Out of the 80 with sustained unsuppressed VL, 58 were switched to second‐line, the remaining continued first line. At 18 months’ follow‐up in December 2015, out of the initially 138 with unsuppressed VL, 56 (41%) were in care and virally suppressed, 37 (27%) were in care with unsuppressed VL and the remaining 45 (33%) were lost, dead, transferred to another clinic or without documented VL. Achieving viral resuppression after EAC (adjusted odds ratio (aOR): 5.02; 95% confidence interval: 1.14–22.09; p = 0.033) and being switched to second‐line in case of sustained viremia after EAC (aOR: 7.17; 1.90–27.04; p = 0.004) were associated with being retained in care and virally suppressed at 18 months of follow‐up. Age, gender, education, time on ART and level of VL were not associated. Conclusions : In this study in rural Lesotho, outcomes along the “failure cascade” were poor. To improve outcomes in this vulnerable patient group who fails the last “90”, programmes need to focus on timely EAC and switch to second line for cases with continuous viremia despite EAC.     

Discontinuation of standard first‐line antiretroviral therapy in a cohort of 1434 Malawian children

The standard first‐line antiretroviral (ART) regimen in Malawi for both adults and children is a fixed‐dose combination tablet containing stavudine (d4T), lamivudine (3TC) and nevirapine (NVP). This regimen has been shown to yield satisfactory virologic and immunologic outcomes in children. Published studies have described insights into discontinuation of first‐line regimen and toxicities of ART in adults, but similar studies in paediatric populations are lacking. A retrospective cohort study was undertaken to assess reasons for discontinuation of the standard first‐line ART regimen (d4T/3TC/NVP) in a paediatric population. In total, 1434 patients met eligibility criteria and were included. The cohort had mean and median age at ART initiation of 4.7 years and 2.9 years, respectively (range: 0.1 months‐18.7 years). The gender distribution was 47% female and 53% male. Median follow‐up time on ART was 1.8 years (range: 2 weeks‐3.9 years). A majority (96.2%) of patients were on the standard first‐line ART regimen, while 3.8% (54) were on a different regimen. Twenty‐eight patients (2.0%) were on an alternative first‐line regimen due to toxicities, 22 patients (1.5%) were on a second‐line regimen due to ART failure, and four patients (0.3%) were on a non‐standard regimen for other clinical reasons. Of the 28 patients who experienced toxicities requiring ART regimen change, 60.7% (17) were caused by NVP, 39.3% (11) by d4T, and none by 3TC. The median time from first‐line ART initiation to alternative first‐line ART was two months (range: 10 days‐28.1 months); 60.7% of patients on alternative first‐line ART were male. Average time on ART until switch to second‐line ART regimen was 16.3 months (SD: 9.3 months). The probability of failure after one year on first‐line regimen was 1.6% (95% CI: 0.9‐2.6). There was no compelling evidence in this cohort, representing approximately 10% of all children on ART in Malawi, to support changing the standard paediatric first‐line regimen based on early toxicities or failure. However, experience from the national adult cohort, longer term follow up of the paediatric cohort in this study, emerging data on resistance after single‐dose NVP containing mother to child transmission antiretroviral prophylaxis, and new 2009 World Health Organization ART recommendations may influence national policy change to a different first‐line regimen.     

Adherence to antiretroviral therapy for HIV in sub‐Saharan Africa and Asia: a comparative analysis of two regional cohorts

Introduction : Our understanding of how to achieve optimal long‐term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV‐positive persons receiving ART who were enrolled in a bi‐regional cohort in sub‐Saharan Africa and Asia. Methods : This multicentre prospective study of adults starting first‐line ART assessed patient‐reported adherence at follow‐up clinic visits using a 30‐day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six‐month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. Results : Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06–1.53; p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8–0.9; p = 0.003), use of concomitant medication (OR 1.8, 1.0–3.2; p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1–1.7; p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4–0.9; p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9–2.6; p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low‐ and lower‐middle‐income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3–2.0; p < 0.001), compared to those in upper‐middle or high‐income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3–7.7; p < 0.001) and Asia (OR 9.0, 95% CI 5.0–16.2; p < 0.001). Patient‐reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. Conclusions : Psychosocial factors and health system resources may explain regional differences. Adherence‐enhancing interventions should address patient‐reported barriers tailored to local settings, prioritizing the first years of ART.     

A prospective “test‐and‐treat” demonstration project among people who inject drugs in Vietnam

Introduction

Modelling suggests that early diagnosis and immediate antiretroviral therapy (ART) among key populations would have a substantial impact in reducing HIV transmission and mortality in Vietnam. An implementation research project of “test‐and‐treat” among people who inject drugs (PWID) was developed to inform effective roll‐out of such interventions.

Methods

“Test‐and‐treat” was offered to PWID in two high burden provinces, Thai Nguyen and Thanh Hoa. The interventions comprised the offer of biannual HIV testing and immediate ART, irrespective of CD4 count. PWID were enrolled between April 2014 and July 2015 and followed up for 12 months, and retention, HIV viral load (VL) and risk behaviours were assessed. Retention in care of this prospective cohort was compared with the retention among men enrolled in care in the preceding period (April 2012 to March 2013) at the same clinics when ART was initiated at CD4 cell count ≤350 cells/mm³.

Results

In total, 287 HIV positive PWID started immediate ART. The majority (98%) were men; median age was 34; and median (interquartile range) CD4 count was 199 (50 to 402) cells/mm³. After 12 months, 238 participants (83%) were retained on ART, and 205 achieved viral suppression (<1000 copies/mL) (92% among those in whom VL was measured, 71% overall). Baseline CD4 count ≤100 cells/mm³ and history of imprisonment were associated with lower retention and viral suppression, while engagement in methadone maintenance was associated with higher retention. Retention in care was higher in the “test‐and‐treat” cohort (83%) compared with men enrolled in care in the preceding period (78%), primarily because lost‐to‐follow‐up during pre‐ART care was eliminated. No decline in consistent condom use and clean needle use was observed.

Conclusions

Early ART initiation resulted in successful treatment outcomes among PWID, with no observed increase in self‐reported risk behaviours, suggesting feasibility and potential effectiveness of “test‐and‐treat” approach. The results also call for differentiated care for PWID, including promoting early diagnosis and engagement in methadone maintenance therapy while enhancing care for those with advanced HIV disease and history of imprisonment.

     

HIV viral load as an independent risk factor for tuberculosis in South Africa: collaborative analysis of cohort studies

Introduction : Chronic immune activation due to ongoing HIV replication may lead to impaired immune responses against opportunistic infections such as tuberculosis (TB). We studied the role of HIV replication as a risk factor for incident TB after starting antiretroviral therapy (ART). Methods : We included all HIV‐positive adult patients (≥16 years) in care between 2000 and 2014 at three ART programmes in South Africa. Patients with previous TB were excluded. Missing CD4 cell counts and HIV‐RNA viral loads at ART start (baseline) and during follow‐up were imputed. We used parametric survival models to assess TB incidence (pulmonary and extrapulmonary) by CD4 cell and HIV‐RNA levels, and estimated the rate ratios for TB by including age, sex, baseline viral loads, CD4 cell counts, and WHO clinical stage in the model. We also used Poisson general additive regression models with time‐updated CD4 and HIV‐RNA values, adjusting for age and sex. Results : We included 44,260 patients with a median follow‐up time of 2.7 years (interquartile range [IQR] 1.0–5.0); 3,819 incident TB cases were recorded (8.6%). At baseline, the median age was 34 years (IQR 28–41); 30,675 patients (69.3%) were female. The median CD4 cell count was 156 cells/µL (IQR 79–229) and the median HIV‐RNA viral load 58,000 copies/mL (IQR 6,000–240,000). Overall TB incidence was 26.2/1,000 person‐years (95% confidence interval [CI] 25.3–27.0). Compared to the lowest viral load category (0–999 copies/mL), the adjusted rate ratio for TB was 1.41 (95% CI 1.15–1.75, p < 0.001) in the highest group (>10,000 copies/mL). Time‐updated analyses for CD4/HIV‐RNA confirmed the association of viral load with the risk for TB. Conclusions : Our results indicate that ongoing HIV replication is an important risk factor for TB, regardless of CD4 cell counts, and underline the importance of early ART start and retention on ART.     

Performance of self‐reported HIV status in determining true HIV status among older adults in rural South Africa: a validation study

Introduction : In South Africa, older adults make up a growing proportion of people living with HIV. HIV programmes are likely to reach older South Africans in home‐based interventions where testing is not always feasible. We evaluate the accuracy of self‐reported HIV status, which may provide useful information for targeting interventions or offer an alternative to biomarker testing. Methods : Data were taken from the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI) baseline survey, which was conducted in rural Mpumalanga province, South Africa. A total of 5059 participants aged ≥40 years were interviewed from 2014 to 2015. Self‐reported HIV status and dried bloodspots for HIV biomarker testing were obtained during at‐home interviews. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for self‐reported status compared to “gold standard” biomarker results. Log‐binomial regression explored associations between demographic characteristics, antiretroviral therapy (ART) status and sensitivity of self‐report. Results : Most participants (93%) consented to biomarker testing. Of those with biomarker results, 50.9% reported knowing their HIV status and accurately reported it. PPV of self‐report was 94.1% (95% confidence interval (CI): 92.0–96.0), NPV was 87.2% (95% CI: 86.2–88.2), sensitivity was 51.2% (95% CI: 48.2–54.3) and specificity was 99.0% (95% CI: 98.7–99.4). Participants on ART were more likely to report their HIV‐positive status, and participants reporting false‐negatives were more likely to have older HIV tests. Conclusions : The majority of participants were willing to share their HIV status. False‐negative reports were largely explained by lack of testing, suggesting HIV stigma is retreating in this setting, and that expansion of HIV testing and retesting is still needed in this population. In HIV interventions where testing is not possible, self‐reported status should be considered as a routine first step to establish HIV status.     

Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy,a Randomized Trial

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4 <350 cells/μL). BMD was measured annually at the lumbar spine and hip by dual‐energy X‐ray absorptiometry (DXA). Percent change in BMD by treatment assignment (intent‐to‐treat analysis) was estimated using longitudinal mixed models and linear regression. Baseline and follow‐up DXA scans were available for 399 (195 immediate, 204 deferred) participants (median age 32 years, 80% non‐white, 26% women, median CD4 count 642 cells/μL). ART (most commonly including tenofovir and efavirenz) was used for 95% and 18% of follow‐up in the immediate and deferred ART groups, respectively. Through 2.2 years mean follow‐up, immediate ART resulted in greater BMD declines than deferred ART at the hip (–2.5% versus –1.0%; difference –1.5%, 95% confidence interval [CI] –2.2 to –0.8, p < 0.001) and spine (–1.9% versus –0.4%; difference –1.6%, 95% CI –2.2 to –1.0, p < 0.001). BMD declines were greatest in the first year of ART. In the immediate ART group, spine BMD stabilized after year 1, whereas hip BMD declined progressively over 2 years. After year 1, BMD changes were similar in the immediate and deferred groups. No clinical, HIV‐related, or ART characteristic predicted greater BMD loss in either group. All HIV treatment guidelines now recommend ART initiation at HIV diagnosis because of the reduced risk of serious clinical outcomes. Better understanding of the longer‐term consequences of the observed reductions in BMD is needed. Clinical Trials Registration: NCT00867048. © 2017 American Society for Bone and Mineral Research.     

Five year neurodevelopment outcomes of perinatally HIV‐infected children on early limited or deferred continuous antiretroviral therapy

Introduction

Early antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV‐infected (HIV‐positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long‐term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIV‐infected infants ≤12 weeks of age with CD4 ≥25% were randomized to deferred ART (ART‐Def); immediate time‐limited ART for 40 weeks (ART‐40W) or 96 weeks (ART‐96W). ART was restarted in the time‐limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants.

Methods

A prospective, longitudinal observational study was used. The Griffiths mental development scales (GMDS), which includes six subscales and a global score, were performed at 11, 20, 30, 42 and 60 months, and the Beery‐Buktenica developmental tests for visual motor integration at 60 months. HIV‐exposed uninfected (HEU) and HIV‐unexposed (HU) children were enrolled for comparison. Mixed model repeated measures were used to compare groups over time, using quotients derived from standardized British norms.

Results

In this study, 28 ART‐Def, 35 ART‐40W, 33 ART‐96W CHER children, and 34 HEU and 39 HU controls were enrolled. GMDS scores over five years were similar between the five groups in all subscales except locomotor and general Griffiths (interaction p < 0.001 and p = 0.02 respectively), driven by early lower scores in the ART‐Def arm. At 60 months, scores for all groups were similar in each GMDS scale. However, Beery visual perception scores were significantly lower in HIV‐infected children (mean standard scores: 75.8 ART‐Def, 79.8 ART‐40W, 75.9 ART‐96W) versus 84.4 in HEU and 90.5 in HU (p < 0.01)).

Conclusions

Early locomotor delay in the ART‐Def arm resolved by five years. Neurodevelopmental outcomes at five years in HIV‐infected children on early time‐limited ART were similar to uninfected controls, apart from visual perception where HIV‐infected children scored lower. Poorer visual perception performance warrants further investigation.

     

Hepatitis C Co‐infection and Severity of Liver Disease as Risk Factors for Osteoporotic Fractures Among HIV‐Infected Patients

Osteoporosis is increasingly reported in the aging HIV‐positive population, and co‐infection with hepatitis C virus (HCV) may further increase the risk of osteoporosis. However, it remains unclear whether HCV‐related increased fracture risk is a function of the severity of liver disease. We calculated the time‐updated alanine aminotransferase to platelet ratio index (APRI) score (an indirect marker of hepatic fibrosis) in all HIV‐infected patients enrolled in the Veterans Affairs' Clinical Case Registry between 1984 and 2009. The association between HCV co‐infection and incident osteoporotic fracture (defined as closed wrist, vertebral, or hip fracture) was assessed in univariate and multivariate Cox survival models adjusting for traditional risk factors for osteoporosis and APRI score or the presence of cirrhosis. A total of 772 osteoporotic fractures were identified among 56,660 HIV‐infected patients (98.1% male; 31.3% HCV co‐infected; median age 44.0 years) contributing 305,237 patient‐years of follow‐up. Fracture rates were significantly higher among HIV/HCV patients than HIV‐only patients (2.57 versus 2.07/1000 patient‐years, relative risk = 1.24, p < 0.0001). In a Cox multivariable model including age, race, smoking, drug use, body mass index, and antiretroviral therapy, HCV co‐infection remained an independent predictor of osteoporotic fractures after controlling for presence of cirrhosis (hazard ratio [HR] = 1.32; p < 0.001) or APRI score (HR = 1.30; p = 0.003). Among HIV/HCV co‐infected patients, cirrhosis strongly predicted osteoporotic fractures (HR = 1.65; 95% confidence interval [CI] 1.11–2.44; p = 0.012), but APRI score was a weaker predictor (HR = 1.008; 95% CI 1.002–1.014; p = 0.015). In conclusion, among HIV‐infected patients, severity of liver disease partly explains the HCV‐associated increased risk of osteoporotic fractures. Other determinants of this increased risk remain to be defined. © 2013 American Society for Bone and Mineral Research.     

No significant association between patient self‐reported non‐adherence to antiretrovirals and HIV‐tropism: a preliminary analysis

Nonadherence to antiretroviral therapy (ART) may cause virologic failure and disease progression has been associated with switch of viral coreceptor usage from CCR5 to CXCR4. We aimed to assess the association between patient‐reported non‐adherence and HIV tropism. This is a cross‐sectional analysis. HIV‐tropism was performed within routine clinical practice either at start of ART or at virological failure. Adherence questionnaire includes: how many times ART has been taken during the last month, missed doses in the last week, timing deviation, refill interruption, drug holidays. Demographics, epidemiological data, HIV and ART history, CD4 and HIVRNA were collected. To assess co‐receptor tropism, env V3 genotyping from viremic plasma HIVRNA was performed. For the analysis, dual/mixed viruses were considered as X4. We included 102 individuals: 76% males; median age 42 y (IQR, 37–46); transmission was heterosexual 37%, homosexual 31%, intravenous drug use 29%. Median nadir of CD4 154/mmc (IQR, 53–274), median zenith of HIVRNA 5.26 (4.72–5.70), 46% had AIDS. 124 tropism tests were: 78% R5, 17% X4, 5% dual/mixed. In cases with previous ART, mono/dual ART was found in 26%, median number of regimens was 5 (IQR, 2–10), median time on triple‐ART was 54 months (IQR, 0–123) with median time of HIVRNA <50 c/ml of 16 months (IQR, 6.5–34.9). At HIV‐tropism, median CD4 and HIV RNA were 321/mmc (IQR, 210–436) and 2.65 (IQR, 2.65–4.91), respectively. Median time between adherence questionnaire and HIV‐tropism was 68 days (IQR, 23–116). At adherence questionnaire, median percentage of ART taken during the last month was 100% (IQR, 90–100), 39% reported missed doses in the last week, 40% timing deviation, 7% refill interruption, 17% drug holidays. At univariate analysis, no statistically significant association between non‐adherence and dual/mixed‐X4 viruses was found (p>0.1). Also gender, age, HIV transmission, AIDS, CD4 nadir, HIVRNA zenith, mono/dual ART, and number of ART regimens were not associated with type of tropism. Only longer time with undetectable HIVRNA before tropism test showed a lower probability of dual/mixed‐X4 viruses (OR for each month 0.95; 95% CI 0.90–1.00; p=0.06). No significant association between adherence and HIV‐tropism was found in this preliminary analysis. It is possible that patient self‐reported adherence is not able to capture nonadherence behaviors that underlie more pronounced viral replication which may be necessary for tropism switch.     

Low Compliance in a Health‐Conscience Spending Era Likely Helps Obviates the Need for 6 month BI‐RADS 3 Breast MRI Follow‐up After 1 year

The goal of our IRB‐approved study was to assess if a follow‐up MRI every 6 months for 2 years is the most appropriate short‐interval follow‐up schedule. 203 breast MRI exams were performed from October 2009 to January 2014 as part of a BI‐RADS 3 follow‐up representing 2.6% of all breast MRIs (7,822) performed. We performed a retrospective longitudinal medical records review of compliance; malignancy rate of BI‐RADS 3 exams; and average time and number of breast MRIs necessary prior to definitive disposition. While 77.8% eventually returned, only 45.5% of patients were compliant with follow‐up at or near 6 months (4.5–7.5 months). Of those who eventually returned, it took an average of 1.31 follow‐up MRIs (95% CI: 1.20–1.43 exams) and 10.3 months (95% CI: 9.0–11.7 months) before definitive disposition. 93.5% of initial findings were dispositioned as benign after two follow‐up MRI exams (malignancy rate: 0.98%). Our results lend support to the possibility that the follow‐up interval for BI‐RADS 3 breast MRIs could be lengthened to 12 months if additional follow‐up MRIs are necessary after the first year of 6‐month follow‐up breast MRIs. Foremost, this appears to be a safe follow‐up alternative since benign definitive disposition can usually be made in less than 1 year. Supplemental reasons include persistent low‐patient compliance (as redemonstrated in our study) and the higher cost of breast MRI compared to mammogram/ultrasound follow‐up. Finally, this paper's findings further support the suggested MRI follow‐up interval in the newest BI‐RADS atlas.