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.     

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.     

Lack of awareness of treatment failure among HIV-1-infected patients in Guinea-Bissau – a retrospective cohort study

Introduction

With more people receiving antiretroviral treatment (ART), the need to detect treatment failure and switch to second-line ART has also increased. We assessed CD4 cell counts (as a marker of treatment failure), determined the rate of switching to second-line treatment and evaluated mortality related to treatment failure among HIV-infected patients in Guinea-Bissau.

Methods

In this retrospective cohort study, adult patients infected with HIV-1 receiving ≥6 months of ART at an HIV clinic in Bissau were included from June 2005 to July 2014 and followed until January 2015. Treatment failure was defined as 1) a fall in CD4 count to baseline (or below) or 2) CD4 levels persistently below 100 cells/µL after ≥6 months of ART. Cox hazard models, with time since six months of ART as the time-varying coefficient, were used to estimate the hazard ratio for death and loss to follow-up.

Results

We assessed 1,591 HIV-1-infected patients for immunological treatment failure. Treatment failure could not be determined in 594 patients (37.3%) because of missing CD4 cell counts. Among the remaining 997 patients, 393 (39.4%) experienced failure. Only 39 patients (9.9%) with failure were switched from first- to second-line ART. The overall switching rate was 3.1 per 100 person-years. Mortality rate was higher in patients with than without treatment failure, with adjusted hazard rate ratios (HRRs) 10.0 (95% CI: 0.9–107.8), 7.6 (95% CI: 1.6–35.5) and 3.1 (95% CI: 1.5–6.3) in the first, second and following years, respectively. During the first year of follow-up, patients experiencing treatment failure had a higher risk of being lost to follow-up than patients not experiencing treatment failure (adjusted HRR 4.4; 95% CI: 1.7–11.8).

Conclusions

We found a high rate of treatment failure, an alarmingly high number of patients for whom treatment failure could not be assessed, and a low rate of switching to a second-line therapy. These factors could lead to an increased risk of resistance development and excess mortality.     

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.     

The treatment outcomes of antiretroviral substitutions in routine clinical settings in Asia; data from the TREAT Asia HIV Observational Database (TAHOD)

Introduction

Although substitutions of antiretroviral regimen are generally safe, most data on substitutions are based on results from clinical trials. The objective of this study was to evaluate the treatment outcomes of substituting antiretroviral regimen in virologically suppressed HIV ‐infected patients in non‐clinical trial settings in Asian countries.

Methods

The study population consisted of HIV ‐infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD ). Individuals were included in this analysis if they started combination antiretroviral treatment (cART ) after 2002, were being treated at a centre that documented a median rate of viral load monitoring ≥0.8 tests/patient/year among TAHOD enrolees, and experienced a minor or major treatment substitution while on virally suppressive cART . The primary endpoint to evaluate outcomes was clinical or virological failure (VF), followed by an ART class change. Clinical failure was defined as death or an AIDS diagnosis. VF was defined as confirmed viral load measurements ≥400 copies/mL followed by an ART class change within six months. Minor regimen substitutions were defined as within‐class changes and major regimen substitutions were defined as changes to a drug class. The patterns of substitutions and rate of clinical or VF after substitutions were analyzed.

Results

Of 3994 adults who started ART after 2002, 3119 (78.1%) had at least one period of virological suppression. Among these, 1170 (37.5%) underwent a minor regimen substitution, and 296 (9.5%) underwent a major regimen substitution during suppression. The rates of clinical or VF were 1.48/100 person years (95% CI 1.14 to 1.91) in the minor substitution group, 2.85/100 person years (95% CI 1.88 to 4.33) in the major substitution group and 2.53/100 person years (95% CI 2.20 to 2.92) among patients that did not undergo a treatment substitution.

Conclusions

The rate of clinical or VF was low in both major and minor substitution groups, showing that regimen substitution is generally effective in non‐clinical trial settings in Asian countries.

     

The cost‐effectiveness of HIV pre‐exposure prophylaxis in men who have sex with men and transgender women at high risk of HIV infection in Brazil

Introduction

Men who have sex with men (MSM) and transgender women (TGW) in Brazil experience high rates of HIV infection. We examined the clinical and economic outcomes of implementing a pre‐exposure prophylaxis (PrEP) programme in these populations.

Methods

We used the Cost‐Effectiveness of Preventing AIDS Complications (CEPAC)‐International model of HIV prevention and treatment to evaluate two strategies: the current standard of care (SOC) in Brazil, including universal ART access (No PrEP strategy); and the current SOC plus daily tenofovir/emtracitabine PrEP (PrEP strategy) until age 50. Mean age (31 years, SD 8.4 years), age‐stratified annual HIV incidence (age ≤ 40 years: 4.3/100 PY; age > 40 years: 1.0/100 PY), PrEP effectiveness (43% HIV incidence reduction) and PrEP drug costs ($23/month) were from Brazil‐based sources. The analysis focused on direct medical costs of HIV care. We measured the comparative value of PrEP in 2015 United States dollars (USD) per year of life saved (YLS). Willingness‐to‐pay threshold was based on Brazil's annual per capita gross domestic product (GDP; 2015: $8540 USD).

Results

Lifetime HIV infection risk among high‐risk MSM and TGW was 50.5% with No PrEP and decreased to 40.1% with PrEP. PrEP increased per‐person undiscounted (discounted) life expectancy from 36.8 (20.7) years to 41.0 (22.4) years and lifetime discounted HIV‐related medical costs from $4100 to $8420, which led to an incremental cost‐effectiveness ratio (ICER) of $2530/YLS. PrEP remained cost‐effective (<1x GDP) under plausible variation in key parameters, including PrEP effectiveness and cost, initial cohort age and HIV testing frequency on/off PrEP.

Conclusion

Daily tenofovir/emtracitabine PrEP among MSM and TGW at high risk of HIV infection in Brazil would increase life expectancy and be highly cost‐effective.

     

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.     

Trastuzumab Beyond Progression for HER2 Positive Metastatic Breast Cancer: Progression‐Free Survival on First‐Line Therapy Predicts Overall Survival Impact

Trastuzumab beyond first progression in the metastatic setting has been adopted based on limited data suggesting improved outcomes compared to second‐line chemotherapy alone although predictive factors for preferential benefit remain elusive. We conducted a retrospective review of all patients receiving trastuzumab for HER2 + metastatic disease between Jan 1, 1999–June 15, 2011. Univariate and time to event analyses described treatment and survival patterns. Median duration of each line of therapy and overall survival times for covariates, including treatment era (pre versus post Jan 1, 2005), lines of trastuzumab‐based therapy (1 versus 2 versus 3 + ), first‐line chemotherapy partner (docetaxel/paclitaxel versus other) and median exposure to first‐line trastuzumab‐based therapy (=/> versus < cohort median) were estimated. A total of 119 patients received a median of two lines of trastuzumab‐based therapy (range 1–8). Median overall survival was 21.8 months (95% CI = 14.5–27.1 m), by era was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m; p = 0.11) and by lines of trastuzumab‐based therapy received was 10.6 m (95% CI = 5.3–17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) (p = 0.0014). Median overall survival was significantly longer for those receiving taxanes with trastuzumab compared to other first line partners (26.1 m, 95% CI = 17.8–31.4 m versus 14.5 m, 95% CI = 9.4–21.9 m, p = 0.02). Median overall survival with duration of first‐line trastuzumab‐based therapy =/> cohort median was 31.9 m (95% CI = 26.2–52.2 m) versus 10.3 m for shorter durations (95% CI = 6.9–15.6 m; p < 0.0001). Our observations support progression‐free survival on first‐line trastuzumab‐based therapy as a clinically relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy.     

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.

     

Outcomes in patients with chronic leg wounds in Denmark: A nationwide register-based cohort study

This study aimed to investigate incidence and predictors of wound healing, relapse, major amputation, and/or death among patients with chronic leg wounds who were referred to specialist treatment at hospital for their condition. A nationwide register-based cohort study design was applied with 5 years of follow-up. All patients with diagnoses of chronic leg wounds in Denmark between 2007 and 2012 were included (n = 8394). Clinical, social, and demographic individual-level linked data from several Danish national registries were retrieved. Incidence rate per 1000 person-years (PY) was calculated. Predictors were investigated using Cox proportional hazards regression analysis. Incidence rates of having a healed wound was 236 per 1000 PY. For relapse, the incidence rate was 75 per 1000 PY, for amputation 16 per 1000 PY, and for death 100 per 1000 PY. Diabetes, peripheral arteria disease, or other comorbidities were associated with decreased chance of wound healing and increased risk of relapse, major amputation, and death. Regional differences in all four outcomes were detected. Basic or vocational education independently predicted risk of amputation and death. This study provides epidemiological data that may help identify patients at particular risk of poor outcomes. It also elucidates social inequality in outcomes.     

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.     

Outcomes after switching from one bisphosphonate to another in 146 patients at a single university hospital

Summary  Most patients who switched to a second bisphosphonate continued their treatment long term, although those who stopped their first drug because of adverse events were likely to discontinue the second drug for the same reason. Switching to another bisphosphonate is a reasonable treatment option for some patients with treatment failure. Introduction  Patients who experience treatment failure with a bisphosphonate because of adverse events (AEs) or other reasons might receive a second bisphosphonate. However, the frequency and benefits of switching bisphosphonates are unknown. Methods  We retrospectively evaluated 197 men and 1110 women newly treated with bisphosphonates between 1 January 2000 and 30 June 2005 at our university hospital. Results  Among the 497 patients who discontinued bisphosphonate treatment, 146 were switched to a second bisphosphonate. The cumulative probabilities of persistence of treatment after 3 years were 45% with the first bisphosphonate and 65% with the second (P = 0.017). Age ≥65 years, switching bisphosphonates because of AEs, and male gender were associated (P < 0.05) with low persistence of treatment with the second bisphosphonate. Discontinuation of the first drug because of AEs was associated with an increased rate of discontinuation of the second drug because of AEs (hazard ratio, 4.2; 95% confidence interval, 2.1–8.4). Conclusions  Patients who switched bisphosphonates had high rates of persistence of therapy. Those who stopped their first bisphosphonate because of AEs were at risk of discontinuing the second drug for the same reason. Switching to another bisphosphonate is a reasonable treatment option for some patients with treatment failure. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Cancer risk with alemtuzumab following kidney transplantation

Alemtuzumab has been employed for induction therapy in kidney transplantation with low rates of acute rejection and excellent graft and patient survival. Antibody induction therapy has been linked to increased vulnerability to cancer. Data regarding malignancy rates with alemtuzumab are limited. We studied 1350 kidney transplant recipients (between 2001 and 2009) at the University of Pittsburgh Starzl Transplant Institute, for post‐transplant de novo and recurrent malignancy, excluding non‐melanoma skin cancer, among patients receiving alemtuzumab, thymoglobulin, and no induction therapies. Of the 1350 patients, 1002 (74.2%) received alemtuzumab, 205 (15.2%) received thymoglobulin, and 122 (9%) received no induction therapy. After excluding cancers occurring within 60 d post‐transplantation, 43 (3.25%) malignancies were observed during a median follow‐up time of 4.0 yr. The incidence of malignancy was 5.4% (1.09 per 100 patient‐years [PY]) with thymoglobulin, 2.8% (0.74 per 100 PY) with alemtuzumab, and 3.3% (0.66 per 100 PY) with no induction (across all groups; p = 0.2342, thymoglobulin vs. alemtuzumab; p = 0.008). Thus, with the exception of non‐melanoma skin cancer which we did not evaluate, alemtuzumab induction was not associated with increased cancer incidence post‐kidney transplantation when compared to no induction therapy and was associated with lower cancer incidence when compared to thymoglobulin.     

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.     

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.     

Temporal trends of time to antiretroviral treatment initiation,interruption and modification: examination of patients diagnosed with advanced HIV in Australia

Introduction

HIV prevention strategies are moving towards reducing plasma HIV RNA viral load in all HIV-positive persons, including those undiagnosed, treatment naïve, on or off antiretroviral therapy. A proxy population for those undiagnosed are patients that present late to care with advanced HIV. The objectives of this analysis are to examine factors associated with patients presenting with advanced HIV, and establish rates of treatment interruption and modification after initiating ART.

Methods

We deterministically linked records from the Australian HIV Observational Database to the Australian National HIV Registry to obtain information related to HIV diagnosis. Logistic regression was used to identify factors associated with advanced HIV diagnosis. We used survival methods to evaluate rates of ART initiation by diagnosis CD4 count strata and by calendar year of HIV diagnosis. Cox models were used to determine hazard of first ART treatment interruption (duration >30 days) and time to first major ART modification.

Results

Factors associated (p<0.05) with increased odds of advanced HIV diagnosis were sex, older age, heterosexual mode of HIV exposure, born overseas and rural–regional care setting. Earlier initiation of ART occurred at higher rates in later periods (2007–2012) in all diagnosis CD4 count groups. We found an 83% (69, 91%) reduction in the hazard of first treatment interruption comparing 2007–2012 versus 1996–2001 (p<0.001), and no difference in ART modification for patients diagnosed with advanced HIV.

Conclusions

Recent HIV diagnoses are initiating therapy earlier in all diagnosis CD4 cell count groups, potentially lowering community viral load compared to earlier time periods. We found a marked reduction in the hazard of first treatment interruption, and found no difference in rates of major modification to ART by HIV presentation status in recent periods.     

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.     

Identification and interference of intraoperative distractions and interruptions in operating rooms

Background

Intraoperative interruptions potentially interfere with surgical flow, contribute to patient safety risks, and increase stress. This study aimed to observe interruption events in operating rooms (ORs) and to measure surgical team's intraoperative interference from interruptions during surgery.

Materials and methods

Sixty-five surgical cases were observed at two surgical clinics in Germany (mainly abdominal and orthopedic surgery). An established observational tool was successfully adapted to German ORs. Various disruptions to surgical work were captured with a predefined coding scheme. In addition, the severity of each observed interruption was rated on behaviorally anchored scale to define the level of OR team involvement. Pilot test supported tools' reliability.

Results

Mean intraoperative duration was 1 h, 23 min (standard deviation = 50:55 min). Overall N = 803 intraoperative interruptions and disruption events were observed. Most frequent were people entering or exiting the OR and telephone or beeper calls. On average, OR teams were distracted or interrupted 9.82 times per hour (standard deviation = 3.97). Equipment failures and OR-environment–related disruptions were rated as the highest interference of OR team functioning. The involved OR professions were differently affected by interruption events. Distribution of intraoperative interruptions within the procedure varied significantly; during early stages of the case, significantly more interruptions were observed.

Conclusions

The study demonstrates the high level of interference in ORs. Furthermore, it provides a useful measure for intraoperative workflow disruptions and their interference of OR team functioning. OR environments need to be well designed to reduce unnecessary interruptions and distractions, so that surgical teams can manage their surgical tasks efficiently and safely.