Changes in second‐line regimen durability and continuity of care in relation to national ART guideline changes in South Africa

Introduction : Little is known about the impact of antiretroviral therapy (ART) guideline changes on the durability of second‐line ART and continuity of care. This study examines predictors of early drug substitutions and treatment interruptions using a cohort analysis of HIV positive adults switched to second‐line ART between January 2004 and September 2013 in Johannesburg, South Africa. Methods : The main outcomes were having a drug substitution or treatment interruption in the first 24 months on second‐line ART. Kaplan Meiers analyses and Cox proportional hazards regression were used to identify predictors of drug substitutions and treatment interruptions. Results : Of 3028 patients on second‐line ART, 353 (11.7%) had a drug substitution (8.6 per 100PY, 95% CI: 7.8–9.6) and 260 (8.6%) had a treatment interruption (6.3 per 100PY, 95% CI: 5.6–7.1). While treatment interruptions decreased from 32.5 per 100PY for the 2004 cohort to 2.3 per 100PY for the 2013 cohort, the rates of drug substitutions steadily increased, peaking at an incidence of 26.7 per 100PY for the 2009 cohort and then decreased to 4.2 per 100PY in the 2011 cohort. Compared to the 2004 to 2008 cohorts, the hazard of early drug substitutions was highest among patients switched to AZT + ddI + LPVr in 2009 to 2010 (aHR 5.1, 95% CI: 3.4–7.1) but remained low over time among patients switched to TDF + 3TC/FTC + LPVr or AZT/ABC + 3TC + LPVr. The main common predictor of both treatment interruption and drug substitution was drug toxicity. Conclusions : Our results show a rapid transition between 2004 and 2010 ART guidelines and concurrent improvements in continuity of care among second‐line ART patients. Drug toxicity reporting and monitoring systems need improvements to inform timely regimen changes and ensure that patients remain in care. However, reasons for drug substitutions should be closely monitored to ensure that patients do not run out of treatment options in the future.     

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.     

广西壮族自治区一线抗病毒方案治疗儿童艾滋病患者的临床特点及疗效分析

目的描述和评价广西壮族自治区接受一线高效抗反转录病毒治疗方案的儿童艾滋病患者的临床特点及疗效。方法以68例以往未接受过抗反转录病毒治疗的儿童艾滋病患者作为研究对象进行队列分析,对治疗基线以及治疗后每3～6个月患儿的CD4+T淋巴细胞百分比以及病毒载量进行统计分析,以评估该组儿童艾滋病患者抗病毒治疗效果。结果患儿平均年龄为3岁(0.2～8岁),其中男39例,女29例,感染途径皆为母婴传播。高效抗反转录病毒治疗方案:行AZT+3TC+NVP者52例,D4T+3TC+NVP者16例。患儿接受抗反转录病毒治疗后,CD4+T淋巴细胞百分比显著升高,治疗满12个月、24个月、36个月的患儿CD4+T淋巴细胞百分比分别为23.8%、28.0%、30.0%。治疗1年以上,病毒载量控制在400拷贝/ml以下的患儿比例为62%～83%。结论在资源有限地区,规范使用一线AZT/D4T+3TC+NVP方案,可以明显改善儿童艾滋病患者免疫学和病毒学状况。     

Virological outcomes of antiretroviral therapy in Zomba central prison,Malawi; a cross‐sectional study

Introduction : Antiretroviral therapy (ART) outcomes that include viral suppression rates are rarely reported among African prison populations. Prisoners deal with specific challenges concerning adherence to ART. We aimed to describe virological outcomes of ART in a large prison in Malawi. Methods : A cross‐sectional study of ART outcomes was conducted at the Zomba Central Prison HIV clinic, Malawi, following the introduction of routine viral load monitoring. All prisoners on ART for at least 6 months were eligible for a viral load test. Patients with ≥1,000 copies/ml received adherence support for 3 months, after which a second VL sample was taken. Patients with ≥5,000 copies/ml on the second sample had virological failure and started 2nd line ART. We describe demographics and patient characteristics and report prevalence of potential‐ and documented virological failure. In the potential virological failure rate, those who could not be sampled after 3 months adherence support are included as virological failures. Logistic regression analysis was used to determine factors associated with potential ART failure. Results and discussion : Viral load testing was started at the end of 2014, when 1054 patients had ever registered on ART. Of those, 501 (47.5%) had transferred out to another clinic, 96 (9.1%) had died, 11 defaulted (1.0%) and 3 (0.3%) stopped ART. Of 443 (42.0%) remaining alive in care, an estimated 322 prisoners were on ART >6 months, of whom 262 (81.4%) were sampled. Their median age was 35 years (IQR 31–40) and 257 (98.1%) were male. Self‐reported adherence was good in 258 (98.5%). The rate of potential ART failure was 8.0%, documented ART failure was 4.6% and documented HIV suppression 95.0%. No patient characteristics were independently associated with potential ART failure, possibly due to low numbers with this outcome. Conclusions : Good virological suppression rates can be achieved among Malawian prisoners on ART, under challenging circumstances.     

The cost‐effectiveness and budgetary impact of a dolutegravir‐based regimen as first‐line treatment of HIV infection in India

Introduction

Dolutegravir (DTG)‐based antiretroviral therapy (ART) is recommended for first‐line HIV treatment in the US and Europe. Efavirenz (EFV)‐based regimens remain the standard of care (SOC) in India. We examined the clinical and economic impact of DTG‐based first‐line ART in the setting of India's recent guidelines change to treating all patients with HIV infection regardless of CD4 count.

Methods

We used a microsimulation of HIV disease, the Cost‐Effectiveness of Preventing AIDS Complications (CEPAC)‐International model, to project outcomes in ART‐naive patients under two strategies: (1) SOC: EFV/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC); and (2) DTG: DTG + TDF/3TC. Regimen‐specific inputs, including virologic suppression at 48 weeks (SOC: 82% vs. DTG: 90%) and annual costs ($98 vs. $102), were informed by clinical trial data and other sources and varied widely in sensitivity analysis. We compared incremental cost‐effectiveness ratios (ICERs), measured in $/year of life saved (YLS), to India's per capita gross domestic product ($1600 in 2015). We compared the budget impact and HIV transmission effects of the two strategies for the estimated 444,000 and 916,000 patients likely to initiate ART in India over the next 2 and 5 years.

Results

Compared to SOC, DTG improved 5‐year survival from 76.7% to 83.0%, increased life expectancy from 22.0 to 24.8 years (14.0 to 15.5 years, discounted), averted 13,000 transmitted HIV infections over 5 years, increased discounted lifetime care costs from $3040 to $3240, and resulted in a lifetime ICER of $130/YLS, less than 10% of India's per capita GDP in 2015. DTG maintained an ICER below 50% of India's per capita GDP as long as the annual three‐drug regimen cost was ≤$180/year. Over a 2‐ or 5‐year horizon, total undiscounted outlays for HIV‐related care were virtually the same for both strategies.

Conclusions

A generic DTG‐based regimen is likely to be cost‐effective and should be recommended for initial therapy of HIV infection in India.

     

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.     

Increases in regimen durability associated with the introduction of tenofovir at a large public-sector clinic in Johannesburg,South Africa

Introduction

In April 2010, tenofovir replaced stavudine in public-sector first-line antiretroviral therapy (ART) in South Africa. The association of tenofovir with fewer side effects and toxicities compared to stavudine could translate to increased durability of tenofovir-based regimens. We evaluated changes over time in regimen durability at the Themba Lethu Clinic, Johannesburg, South Africa.

Methods

This was a cohort analysis of treatment-naïve, non-pregnant adult patients initiated on ART between April 2004 and December 2011. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir was substituted for stavudine after April 2010. We evaluated the frequency and type of single-drug substitutions (excluding switches to second-line therapy). Cox models were used to evaluate the association of ART initiation year and antiretroviral drug type with single-drug substitutions in the first 12 months on treatment.

Results

One thousand nine hundred and sixty-four (10%) substitutions occurred amongst 19,699 patients. Excluding 2004 (year of treatment roll-out), before 2010 one-year single-drug substitutions ranged from 10.0 to 13.1%. In 2011, well after integration of tenofovir, substitutions decreased to 5.6%. Single-drug substitution was lowest amongst patients on tenofovir (5.1%) versus zidovudine (11.3%), 30 mg stavudine (10.5%) or 40 mg stavudine (14.4%). Adjusted Cox models showed that patients initiating treatment between 2005 and 2010 (vs. 2011) had a twofold increased hazard of single-drug substitution, while those on zidovudine or stavudine had a two to threefold increase in single-drug substitution versus tenofovir patients in the first 12 months on ART.

Conclusions

The decline in single-drug substitutions is associated with the introduction of tenofovir. Tenofovir use could improve regimen durability and treatment outcomes in resource-limited settings.     

Impact of Everolimus and Low‐Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR‐based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low‐dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard‐dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high‐risk (donor+/recipient?) patients (n = 88), the EVR‐based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val‐)ganciclovir (n = 63), the CMV‐free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR‐based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard‐dose calcineurin inhibitor–based regimen.     

Early virological response to HIV treatment: can we predict who is likely to experience subsequent treatment failure? Results from an observational cohort study,London, UK

Introduction : For people living with HIV, the first antiretroviral treatment (ART) regimen offers the best chance for a good virological response. Early identification of those unlikely to respond to first‐line ART could enable timely intervention and increase chances of a good initial treatment response. In this study we assess the extent to which the HIV RNA viral load (VL) at 1 and 3 months is predictive of first‐line treatment outcome at 6 months. Methods : All previously ART‐naive individuals starting ART at two London centres since 2000 with baseline (−180 to 3 days) VL >500 c/mL had a VL measurement between 6 and 12 months after starting ART, and at least one at month 1 (4–60 days) or month 3 (61–120 days) were included. Lack of treatment response was defined as (i) VL >200 copies/mL at 6 months or (ii) VL >200 copies/mL at 6 months or simultaneous switch in drugs from at least two different drug classes before 6 months. The association with VL measurements at 1 and 3 months post‐ART; change from pre‐ART in these values; and CD4 count measurements at 1 and 3 months were assessed using logistic regression models. The relative fit of the models was compared using the Akaike information criterion (AIC). Results : A total of 198 out of 3258 individuals (6%) experienced lack of treatment response at 6 months (definition i), increasing to 511 (16%) for definition (ii). Those with a 1‐month (day 4–60 window) VL of <1000, 1000–9999, 10,000–99,999 and >100,000 copies/ml had a 4%, 8%, 23% and 24% chance, respectively, of subsequently experiencing treatment non‐response at 6 months (definition (i)). When considering the 3‐month (day 61–120 window) VL, the chances of subsequently experiencing treatment non‐response were, respectively, 3%, 25%, 67% and 75%. Results were similar for definition (ii). Conclusions : Whilst 3‐month VL provides good discrimination between low and high risk of treatment failure, 1‐month VL does not. Presence of a VL >10,000 copies/ml after 3 months of ART is a cutoff above which individuals are at a sufficiently higher risk of non‐response that they may be considered for intervention.     

The relation between efavirenz versus nevirapine and virologic failure in Johannesburg,South Africa

Introduction

Previous research has raised concerns that patients given nevirapine (NVP)-based regimens experience more virologic failure than patients given efavirenz (EFV)-based regimens. We investigated this hypothesis in a cohort of HIV-positive patients at a large HIV treatment clinic in South Africa.

Methods

All antiretroviral therapy (ART)-naïve non-pregnant patients, ≥18 years old, without tuberculosis, who initiated treatment with either NVP or EFV from April 2004 to August 2011 at the Themba Lethu Clinic in Johannesburg, South Africa, were included. Log-binomial regression and modified Poisson regression were used to estimate risk ratios (RR) with 95% confidence intervals (CI) for predictors of virologic failure, virologic suppression, and loss to follow-up (LTF), whereas a Cox proportional hazards model was used to estimate the risk of death, all within one year.

Results

Of 12,840 included patients, 62.0% were female and the median baseline CD4 count was 98 cells/mm³ (36–169). Of these patients, 93.2% initiated an EFV-based regimen. After adjusting for baseline characteristics, no difference in death (adjusted Hazards Ratio (aHR): 0.92; 95% CI: 0.68–1.25), LTF (adjusted Risk Ratio (aRR): 1.00; 95% CI: 0.79–1.25), nor suppression (aRR: 0.98; 95% CI: 0.95–1.00) at one year was found between regimens. Among patients with ≥1 viral load ≥4 months after ART initiation, 4% (n=350) experienced virologic failure within 12 months of initiation. Patients initiating NVP-based regimens were 60% more likely to fail than patients initiating EFV-based regimens (aRR: 1.58; 95% CI: 1.13–2.22).

Conclusions

In this cohort, patients initiating NVP-based regimens experienced more virologic failure than patients initiating EFV-based regimens. Future guidelines should consider the implications of different efficacy profiles when making recommendations for which drugs to prioritize.     

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.     

HIV transmission and retention in care among HIV‐exposed children enrolled in Malawi's prevention of mother‐to‐child transmission programme

Introduction : In Malawi, HIV‐infected pregnant and breastfeeding women are offered lifelong antiretroviral therapy (ART) regardless of CD4 count or clinical stage (Option B+). Their HIV‐exposed children are enrolled in the national prevention of mother‐to‐child transmission (PMTCT) programme, but many are lost to follow‐up. We estimated the cumulative incidence of vertical HIV transmission, taking loss to follow‐up into account. Methods : We abstracted data from HIV‐exposed children enrolled into care between September 2011 and June 2014 from patient records at 21 health facilities in central and southern Malawi. We used competing risk models to estimate the probability of loss to follow‐up, death, ART initiation and discharge, and used pooled logistic regression and inverse probability of censoring weighting to estimate the vertical HIV transmission risk. Results : A total of 11,285 children were included; 9285 (82%) were born to women who initiated ART during pregnancy. At age 30 months, an estimated 57.9% (95% CI 56.6–59.2) of children were lost to follow‐up, 0.8% (0.6–1.0) had died, 2.6% (2.3–3.0) initiated ART, 36.5% (35.2–37.9) were discharged HIV‐negative and 2.2% (1.5–2.8) continued follow‐up. We estimated that 5.3% (95% CI 4.7–5.9) of the children who enrolled were HIV‐infected by the age of 30 months, but only about half of these children (2.6%; 95% CI 2.3–2.9) were diagnosed. Conclusions : Confirmed mother‐to‐child transmission rates were low, but due to poor retention only about half of HIV‐infected children were diagnosed. Tracing of children lost to follow‐up and HIV testing in outpatient clinics should be scaled up to ensure that all HIV‐positive children have access to early ART.     

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.     

Adherence and retention on antiretroviral therapy in a public‐private partnership program in Nigeria

Initiation of HIV‐positive patients on antiretroviral therapy (ART) in Nigeria was restricted to secondary and tertiary level hospitals due to weak health systems in primary health centres (PHCs). Shell Petroleum Development Company (SDPC) Nigeria and FHI 360 using a systems strengthening approach, piloted ART enrolment in a PHC in south‐eastern Nigeria. This study sought to evaluate patients’ adherence and mortality on ART, and associated risk factors. We reviewed clinic records of adult patients initiating ART between January 2007 and December 2009. Adherence was calculated as the number of days of medication dispensed as a percentage of total number of days evaluated. Outcome measures were probability of being alive and retained in care at 12 and 24 months on ART. Competing risks regression models were used to assess potential predictors associated with mortality. Total of 196 patients (64.8% males) were initiated on ART. Patients’ median age was 35 years (IQR 30–44); median CD4 at initiation was 132 cells/mm³ (IQR 82–212), Patients in WHO stage III and IV constituted 73 (37.6%) and 83 (42.8%) respectively. Majority (108 [55.1%]) of patients had adherence rates >95%. Adherence levels ranged: 70–85%, 50–65% and <50% in 29 (14.8%), 30 (15.3%) and 29 (14.8%) of patients respectively. Nucleoside backbone use were AZT/3TC (69.4%) d4T/3TC (28.6%) and TDF/FTC (2%). At 12 months of follow up, 80.6% (158) were alive and on ART, mortality accounted for 12.8% (25), 11 (5.6%) were LTFU and 2 (1.1%) transferred out. At 24 months on ART survival decreased to 64.3% (126), 20.4% (40) died, 9.2% (18) were LTFU and 12 (6.1%) transferred out. Competing risks regression models revealed that patients’ factors significantly associated with mortality include: bedridden patients (HR=3.6 [95% CI: 1.11–11.45], p=0.03, referent: working), <50% adherence levels (HR=27.7 [95% CI: 8.55–89.47], p<0.0001, referent: >95% adherence level). In conclusion, majority of attrition was due to mortality. Poor adherence was associated with 27 times higher risk of death compared with patients with >95% adherence. Mortality is likely to reduce by establishing a more robust adherence counselling process.     

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.     

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.     

Transitioning young adults from paediatric to adult care and the HIV care continuum in Atlanta,Georgia, USA: a retrospective cohort study

Introduction : The transition from paediatric to adult HIV care is a particularly high‐risk time for disengagement among young adults; however, empirical data are lacking. Methods : We reviewed medical records of 72 youth seen in both the paediatric and the adult clinics of the Grady Infectious Disease Program in Atlanta, Georgia, USA, from 2004 to 2014. We abstracted clinical data on linkage, retention and virologic suppression from the last two years in the paediatric clinic through the first two years in the adult clinic. Results : Of patients with at least one visit scheduled in adult clinic, 97% were eventually seen by an adult provider (median time between last paediatric and first adult clinic visit = 10 months, interquartile range 2–18 months). Half of the patients were enrolled in paediatric care immediately prior to transition, while the other half experienced a gap in paediatric care and re‐enrolled in the clinic as adults. A total of 89% of patients were retained (at least two visits at least three months apart) in the first year and 56% in the second year after transition. Patients who were seen in adult clinic within three months of their last paediatric visit were more likely to be virologically suppressed after transition than those who took longer (Relative risk (RR): 1.76; 95% confidence interval (CI): 1.07–2.9; p = 0.03). Patients with virologic suppression (HIV‐1 RNA below the level of detection of the assay) at the last paediatric visit were also more likely to be suppressed at the most recent adult visit (RR: 2.3; 95% CI: 1.34–3.9; p = 0.002). Conclusions : Retention rates once in adult care, though high initially, declined significantly by the second year after transition. Pre‐transition viral suppression and shorter linkage time between paediatric and adult clinic were associated with better outcomes post‐transition. Optimizing transition will require intensive transition support for patients who are not virologically controlled, as well as support for youth beyond the first year in the adult setting.     

Paclitaxel and cisplatin chemotherapy for metastatic urothelial carcinoma after failure of two courses of platinum‐based regimens

Objectives: We investigated the outcomes of paclitaxel and cisplatin chemotherapy as an optional regimen for patients with metastatic urothelial carcinoma after failure of two consecutive platinum‐based regimens. Methods: We retrospectively analyzed the data of 21 patients who had evidence of disease progression after two consecutive platinum‐based regimens, gemcitabine and cisplatin (GC course), and methotrexate, vinblastine, doxorubicin and cisplatin (M‐VAC course) as first‐line and second‐line treatments. As third‐line chemotherapy, patients received paclitaxel (175 mg/m²) and cisplatin (70 mg/m²) every 3 weeks until disease progression. Results: Complete remission occurred in one patient (4.8%), partial remission occurred in three patients (14.3%) and stable disease occurred in five patients (23.8%). The overall response rate was 19.0% and the overall disease control rate, including stable disease, was 42.9%. The median progression‐free survival (PFS) was 3 months (95% CI 3.0–5.0). The median overall survival was 9 months (95% CI 7.0–15.0). Grade 3 to 4 neutropenia appeared in 85.7% of patients. No life‐threatening complications were observed. Conclusions: Paclitaxel and cisplatin chemotherapy could be an optional regimen for patients with metastatic urothelial carcinoma after the failure of two consecutive standard platinum‐based regimens.     

The next generation of the World Health Organization's global antiretroviral guidance

The 2013 World Health Organization’s (WHO) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection provide more than 50 new recommendations across the continuum of HIV care, including recommendations on HIV testing, using antiretroviral drugs for prevention, linking individuals to HIV care and treatment services, initiating and maintaining antiretroviral therapy (ART) and monitoring treatment. Guidance is provided across all age groups and populations of adults, pregnant and breastfeeding women, adolescents and key populations. The guidelines are based on a public health approach to expanding the use of ARV drugs for HIV treatment and prevention, with a particular focus on resource‐limited settings. The most important new clinical recommendations include: treating adults, adolescents and older children earlier – starting ART in all individuals with a CD4 cell count of 500 cells/mm³ or less (but giving priority to those with advanced clinical disease or a CD4 cell count less than 350 cells/mm³); starting ART at any CD4 cell count in certain populations, including those with active TB (existing recommendation), Hepatitis B infection and severe chronic liver disease, HIV‐positive partners in serodiscordant couples (existing recommendation), pregnant and breastfeeding women, and children younger than 5 years of age; a preferred first‐line ART regimen of Tenofovir+3TC or FTC+ Efavirenz as a once‐daily fixed‐dose combination for adults, pregnant women, and children aged 3 years and older; and the use of viral load testing as the preferred approach to monitoring the response to ART and to diagnose treatment failure. Guidance is also provided on enhancing the efficiency and effectiveness of HIV services, including strategies to improve retention in care, and adherence to ART; task‐shifting to address human resource gaps; decentralizing delivery of ART to primary health care, and integrating ART services within maternal and child health, TB or drug dependency clinics. There is additional guidance for programme managers on how to plan HIV programmes and use resources most efficiently.