Simplified clinical prediction scores to target viral load testing in adults with suspected first line treatment failure in Phnom Penh, Cambodia.

BACKGROUND: For settings with limited laboratory capacity, 2013 World Health Organization (WHO) guidelines recommend targeted HIV-1 viral load (VL) testing to identify virological failure. We previously developed and validated a clinical prediction score (CPS) for targeted VL testing, relying on clinical, adherence and laboratory data. While outperforming the WHO failure criteria, it required substantial calculation and review of all previous laboratory tests. In response, we developed four simplified, less error-prone and broadly applicable CPS versions that can be done 'on the spot'. METHODOLOGY/PRINCIPAL: Findings From May 2010 to June 2011, we validated the original CPS in a non-governmental hospital in Phnom Penh, Cambodia applying the CPS to adults on first-line treatment >1 year. Virological failure was defined as a single VL >1000 copies/ml. The four CPSs included CPS1 with 'current CD4 count' instead of %-decline-from-peak CD4; CPS2 with hemoglobin measurements removed; CPS3 having 'decrease in CD4 count below baseline value' removed; CPS4 was purely clinical. Score development relied on the Spiegelhalter/Knill-Jones method. Variables independently associated with virological failure with a likelihood ratio ≥ 1.5 or ≤ 0.67 were retained. CPS performance was evaluated based on the area-under-the-ROC-curve (AUROC) and 95% confidence intervals (CI). The CPSs were validated in an independent dataset. A total of 1490 individuals (56.6% female, median age: 38 years (interquartile range (IQR 33-44)); median baseline CD4 count: 94 cells/µL (IQR 28-205), median time on antiretroviral therapy 3.6 years (IQR 2.1-5.1)), were included. Forty-five 45 (3.0%) individuals had virological failure. CPS1 yielded an AUROC of 0.69 (95% CI: 0.62-0.75) in validation, CPS2 an AUROC of 0.68 (95% CI: 0.62-0.74), and CPS3, an AUROC of 0.67 (95% CI: 0.61-0.73). The purely clinical CPS4 performed poorly (AUROC-0.59; 95% CI: 0.53-0.65). CONCLUSIONS: Simplified CPSs retained acceptable accuracy as long as current CD4 count testing was included. Ease of field application and field accuracy remains to be defined

Incidence of Treatment-Limiting Toxicity with Stavudine-Based Antiretroviral Therapy in Cambodia: A Retrospective Cohort Study

Background: Although stavudine (D4T) remains frequently used in low-income countries in Asia, associated long-term toxicity data are scarce. The aim of this study was to determine the long-term incidence of severe D4T-toxicity (requiring drug substitution) and associated risk factors in HIV-infected Cambodians up to six years on antiretroviral treatment (ART). Methodology/Principal Findings: This is a retrospective analysis of an observational cohort, using data from an ART program with systematic monitoring for D4T-toxicity. Probabilities of time to D4T substitution due to suspected D4T toxicity (treatment-limiting D4T toxicity) were calculated, a risk factor analysis was performed using multivariate Cox regression modelling. Out of 2581 adults initiating a D4T-containing regimen, D4T was replaced in 276 (10.7%) patients for neuropathy, 14 (0.5%) for lactic acidosis and 957 (37.1%) for lipoatrophy. The main early side effect was peripheral neuropathy (7.0 % by 1 year). After the first year, lipoatrophy became predominant, with a cumulative incidence of 56.1 % and 72.4 % by 3 and 6 years respectively. Older age (aHR 1.8; 95%CI: 1.4–2.3) and lower baseline haemoglobin (aHR 1.7; 95%CI: 1.4–2.2) were associated with the occurrence of neuropathy. Being female (aHR 3.8; 95%CI: 1.1–12.5), a higher baseline BMI (aHR 12.6; 95%CI: 3.7–43.1), and TB treatment at ART initiation (aHR 8.6; 95%CI: 2.7–27.5) increased the likelihood of lactic acidosis. Lipoatrophy was positively associated with female gender (aHR 2.3; 95%CI: 2.0–2.6), an older age (aHR 1.3; 95%CI: 1.1–1.4), and a CD4 count,200 cells/mL (aHR 1.3; 95%CI: 1.1–1.5)

Validation of a clinical prediction score to target viral load testing in adults with suspected first-line treatment failure in resource-constrained settings.

BACKGROUND: Although routine viral load (VL) monitoring currently is too costly for poor countries, clinical failure criteria perform poorly. We previously developed an algorithm combining a clinical predictor score (CPS) with targeted VL testing in a Cambodian patient population (derivation population). We now prospectively validate the algorithm in the same clinical setting (validation population), assess its operational performance, and explore its cost-saving potential. METHODS: We performed a cross-sectional study in a tertiary hospital in Phnom Penh, Cambodia, applying the CPS in adults on first-line antiretroviral treatment for at least 1 year. Treatment failure was defined as a VL >1000 copies per milliliter. The area under the receiver-operating characteristic (AUROC) curve of the CPS to detect treatment failure in the current study population (validation population) was compared with the AUROC of the CPS obtained in the patient population where the CPS was derived from in 2008 in the same study setting (derivation population). Costs related to VL testing and second-line regimens with the different testing strategies were compared. RESULTS: One thousand four hundred ninety individuals {56.6% female, median age 38 years [interquartile range (IQR): 33-44]} were included, with a median baseline CD4 cell count of 94 cells per microliter (IQR: 28-205). Median time on antiretroviral treatment was 3.6 years (IQR: 2.1-5.1), 45 (3.0%) individuals had treatment failure. The AUROC of the CPS in validation was 0.75 (95% confidence interval: 0.67 to 0.83), relative to an AUROC of 0.70 in the derivation population. At the CPS cutoff ≥ 2, VL was indicated for 164 (11%) individuals, preventing inappropriate switching to second line in 143 cases. Twenty-four cases of treatment failure would be missed. When applied in routine care, the AUROC was 0.69 (95% confidence interval: 0.60 to 0.77). Overall 1-year program costs with targeted VL testing were 4-fold reduced. CONCLUSIONS: The algorithm performed well in validation and has cost-saving potential. Further studies to assess its performance, feasibility, and impact in different settings are warranted

Genotypic impact of prolonged detectable HIV type 1 RNA viral load after HAART failure in a CRF01_AE-infected cohort.

HIV subtype-specific data on mutation type, rate, and accumulation following HAART treatment failure are limited. We studied patterns and accrual of drug resistance mutations in a Cambodian CRF01_AE-infected cohort continuing a virologically failing first-line, nonnucleoside reverse transcriptase inhibitor- (NNRTI-) based, HAART. Between 2005 and 2007, 837 adult HIV-infected patients had regular plasma HIV-1 RNA viral load measurements at Sihanouk Hospital Centre of Hope (SHCH), Cambodia. Drug resistance testing was performed in all patients with HIV-1 RNA >1000 copies/ml after at least 6 months of HAART. Seventy-one patients with a mean age of 34 years, of whom 68% were male, were retrospectively assessed at virological failure. The median duration of antiretroviral therapy was 12.3 (IQR 7.1-18.23) months, the median CD4 cell count was 173 (IQR 118-256) cells/mm(3), and the mean plasma HIV-1 RNA viral load was 3.9 log (SD 0.72) at failure. NNRTI mutations, M184I/V mutation, thymidine analogue mutations, and K65R were observed in 78.9%, 69%, 20%, and 12.7% of patients, respectively. For 33 patients, genotypic testing was carried out on at least two occasions before the switch to second-line HAART after a median duration of 5.8 (IQR 4.3-6.1) months of virological failure: 54.5% of patients accumulated new mutations with a rate of 1.6 mutations per person-year. Accumulation was seen both for nucleoside and nonnucleoside reverse transcriptase inhibitors, and also in patients with low-level viremia. Subtype-specific data on mutation type, rate, and accumulation after HAART failure are urgently needed to optimize treatment strategies in resource-limited settings

Baseline characteristics of adult patients initiating stavudine-containing antiretroviral treatment (N = 2581).

<p>IQR: interquartile range, WHO: world health organization, ART: antiretroviral therapy.</p>a<p>From 2006, stavudine was prescribed as 30 mg bid, irrespective of body weight. Prior to that, 40 mg bid was given for individuals with a body weight >60 kg.</p

Risk factors for severe toxicity related to stavudine.

<p>aHR: adjusted hazard ratio, CI: confidence interval, WHO: world health organization, BMI: body mass index, NNRTI: non-nucleoside reverse transcriptase inhibitor; EFV: efavirenz; NVP: nevirapine; TB: tuberculosis; ART: antiretroviral treatment.</p

Diagnostic performance at different cut-offs of the clinical prediction scores to identify virological failure using an independent dataset.

<p>CPS: clinical prediction score; PPV: positive predictive value; % VL done: percentage of patients that would undergo targeted VL testing; LHR: likelihood ratio.</p

Content and diagnostic performance of the simplified clinical prediction scores to identify virological failure^a.

<p>ART: antiretroviral treatment; AUROC: area under the receiver-operating characteristic curve; CPS: clinical prediction score; PPE: papular pruritic eruption; VAS: visual analogue scale.</p>a<p>differences between CPSs in the score of some predictors relate to the fact that the weight of each remaining predictor was recalculated after removing of specific predictors (<i>eg</i> after removing hemoglobin in CPS2 vs CPS1).</p>b<p>over a period of six months prior to viral load measurement.</p>c<p>over a period of one month prior to viral load measurement.</p

Datasets used for the development and validation of the simplified prediction score to identify virological failure.

a<p>Inclusion criteria: consecutive enrolment of adult patients (≥18 years old) in follow-up at the Sihanouk Hospital Center of Hope on first-line ART for at least 12 months; viral load was systematically performed for study purpose; virological failure was defined as a single measurement >1000 copies/ml;</p>b<p>more than one episodes per individual.</p><p>ART: antiretroviral treatment; AZT: zidovudine; D4T: stavudine; 3TC: lamivudine; NVP: nevirapine; EFV: efavirenz; IQR: interquartile range.</p

MODIS-Based Investigation of Flood Areas in Southern Cambodia from 2002–2013

In Cambodia and the Vietnamese Mekong Delta, floods commonly occur during the rainy season, and a better understanding of their spatio-temporal distribution is important for both disaster prevention and the improvement of agricultural production. This study investigated spatio-temporal flood inundation and land cover change from 2002 to 2013 in the southern part of Cambodia using Terra satellite on-board Moderate Resolution Imaging Spectroradiometer (MODIS) images. The algorithm for flood inundation detection, WFFI (Wavelet-based Filter for detecting spatio-temporal changes in Flood Inundation) was used, and the parameters were modified to fit the present study. The estimated inundation areas were validated using eight Landsat images. In a comparison between the original and modified WFFIs, the modified WFFI (70&#8722;96%) exhibited better accuracy than the original WFFI (30&#8722;70%). Overall, the temporal change in the flood inundation area presented a decreasing trend, and a link to the in-situ observed water level showed a decreasing trend during the rainy season. Furthermore, the estimated flood inundation exhibited a significant delay since 2008. Based on the yearly land cover MODIS product, the permanent water body and wetland areas decreased, whereas the cropland areas increased. This was as a result of increased agricultural productivity. However, water shortage was the major obstacle to increasing agricultural productivity, and it also had a negative impact on aquatic ecology, such as fish spawning grounds