CD4 Cell Count Monitoring Research Articles

Pooling Strategies to Reduce the Cost of HIV-1 RNA Load Monitoring in a Resource-Limited Setting

Quantitative human immunodeficiency virus (HIV) RNA load testing surpasses CD4 cell count and clinical monitoring in detecting antiretroviral therapy (ART) failure; however, its cost can be prohibitive. Recently, the use of pooling strategies with a clinically appropriate viral load threshold was shown to be accurate and efficient for monitoring when the prevalence of virologic failure is low. We used laboratory request form information to identify specimens with a low pretest probability of virologic failure. Patients aged ≥15 years who were receiving first-line ART had individual viral load results available were eligible. Blood plasma, dried blood spots, and dried plasma spots were evaluated. Two pooling strategies were compared: minipools of 5 samples and a 10 ×10 matrix platform (liquid plasma specimens only). A deconvolution algorithm was used to identify specimens(s) with detectable viral loads. The virologic failure rate in the study sample was <10%. Specimens included were liquid plasma specimens tested in minipools(n = 400), of which 300 were available for testing by matrix, and specimens tested with minipools only: dried blood spots (n = 100) and dried plasma spots (n = 185). Pooling methods resulted in 30.5%-60% fewer HIV RNA tests required to screen the study sample. For plasma pooling, the matrix strategy had the better efficiency, but minipools of 5 dried blood spots had the best efficiency overall and were accurate at a >95% negative predictive value with minimal technical requirements. In resource-constrained settings, a combination of preselection of patients with low pretest probability of virologic failure and pooled testing can reduce the cost of virologic monitoring without compromising accuracy.

Quantitatively monitoring AIDS policy implementation in China

Background China has been scaling up its national AIDS programs since 2004. We tested a hypothesis that incrementally setting realistic quantitative targets for key indicators and monitoring performance would facilitate AIDS policy implementation in China.Methods Core indicators monitoring the national AIDS program were developed, modified and used from 2007 through 2009. Targets of core indicators were set incrementally and monitored annually. Data were collected and reported from local counties in all 31 provinces of mainland China. Changes of core indicators from 2007 to 2009 were calculated and compared using Cochran–Armitage Trend tests.Results The number of patients receiving free anti-retroviral treatment and methadone maintenance treatment increased from 41 777 to 81 739, from 97 554 to 241 975, respectively, between 2007 and 2009. The proportion of newly reported HIV/AIDS cases with a completed epidemiological investigation increased from 77.7% in 2007 to 91.1% in 2009 (P < 0.0001). The proportion of spouses of newly reported HIV/AIDS cases being tested for HIV increased from 24.7 to 63.4% (P < 0.001). Follow-up visits to people with HIV and AIDS increased from 32.8 and 34.0% in 2007 to 74.6 and 78.5% in 2009, respectively (both P < 0.0001). The proportion of CD4+ cell count monitoring for people with HIV and AIDS increased from 45.3 and 10.1% in 2007 to 54.2 and 62.5% in 2009, respectively (both P < 0.001). Viral load monitoring for AIDS patients receiving anti-retroviral treatment increased from 9.1 to 48.5% (P < 0.001).Conclusions Setting targets for core indicators and monitoring performance has facilitated implementation of the national AIDS program in China.

British HIV Association guidelines for antiretroviral treatment of HIV‐2‐positive individuals 2010

British HIV Association guidelines for antiretroviral treatment of HIV‐2‐positive individuals 2010

Cost-effectiveness of laboratory monitoring in sub-Saharan Africa: a review of the current literature.

As the global community evaluates the unprecedented investment in the scale-up of human immunodeficiency virus (HIV) therapy and considers future investments in HIV care, it is crucial to identify those HIV interventions that maximize the benefit realized from each dollar spent. The use of laboratory monitoring assays--CD4 cell count and HIV RNA level--in decisions about when to initiate and switch antiretroviral therapy may offer substantial clinical benefit, but their economic value remains controversial. Cost-effectiveness analysis can be used to evaluate the value for money of strategies for HIV care, including alternative approaches to laboratory monitoring. Five published cost-effectiveness analyses address the question of CD4 cell count and HIV RNA level monitoring for HIV-infected patients in Africa, with differing conclusions. We describe the use of cost-effectiveness analysis in resource-limited settings and review the cost-effectiveness literature with regard to monitoring the CD4 cell count and HIV RNA level in Africa, highlighting some of the most critical issues in this debate.

Quantifying HIV for Monitoring Antiretroviral Therapy in Resource‐Poor Settings

There is increasing evidence to support the inability of CD4 cell count monitoring to predict virological failure in human immunodeficiency virus-infected individuals receiving antiretroviral therapy. There is renewed interest in improving access to viral load monitoring in resource-constrained regions to monitor adherence to treatment and to switch therapy. The field is rapidly changing as new technology platforms are made available for evaluation. This article presents an up to date summary of the assays available for viral load monitoring and suggests approaches for their implementation.

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial

SummaryBackgroundHIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.MethodsIn this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per μL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per μL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1·18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779.FindingsTwo participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85–88) in the CDM group and 90% (88–91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4·9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6·94 [95% CI 6·33–7·60] vs 5·24 [4·72–5·81] per 100 person-years; absolute difference 1·70 per 100 person-years [0·87–2·54]; HR 1·31 [1·14–1·51]; p=0·0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1·12 [0·94–1·32]; p=0·19), with anaemia the most common (76 vs 61 cases).InterpretationART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment.FundingUK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome

The International Network for the Study of HIV-associated IRIS (INSHI) recently published criteria for tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) diagnosis. The performance of this definition and clinical manifestations of TB-IRIS were studied. Antiretroviral therapy-naive HIV/TB Thai patients receiving antituberculous therapy were enrolled during 2006-2007 and prospectively followed through 24 weeks of antiretroviral therapy. Patients were defined as having paradoxical TB-IRIS if they fulfilled the 'study definition' by French 2004 and were confirmed by an external reviewer. All were later compared by the classification according to 'INSHI-2008'. For the 126 patients, median baseline CD4 cell count was 43 cells/microl and HIV-1 RNA was 5.9 log(10) Y copies/ml. Seventy-three (58%) had extrapulmonary/disseminated TB. Twenty-two (18%) and 21 (17%) fulfilled TB-IRIS criteria according to the study definition and INSHI-2008 definition, respectively. Two (2%) were diagnosed by study definition only and one (1%) by INSHI-2008 definition only. Twenty (16%) were concordantly diagnosed by both definitions and 103 (82%) were consistently negative. Eighteen (82%) had worsening of a preexisting site, whereas four (18%) had TB-IRIS in a new location. Lymph node enlargement (73%) and fever (59%) were common in TB-IRIS. Sensitivity and specificity of INSHI-2008 was 91% (95% confidence interval, 72-98%) and 99% (95% confidence interval, 95-99.8%), respectively. Positive predictive value was 95% and negative predictive value was 98%. By multivariate analysis, factors predicting TB-IRIS were extrapulmonary TB (odds ratio, 8.63) and disseminated TB (odds ratio, 4.17). There was high concordance between the INSHI-2008 and French 2004 definition for TB-IRIS diagnosis in HIV/TB patients with relatively high rate of paradoxical TB-IRIS. This suggests that lack of HIV-1 RNA and CD4 cell count monitoring does not impede the ability to diagnose TB-IRIS.

CD4+ T-Cell Count Monitoring Does Not Accurately Identify HIV-Infected Adults With Virologic Failure Receiving Antiretroviral Therapy

CD4 T-lymphocyte (CD4) counts are widely used to monitor response to antiretroviral therapy (ART) in resource-limited settings. However, the utility of such monitoring in terms of predicting virologic response to therapy has been little studied. We studied participants aged 18 years and older who initiated ART in Tororo, Uganda. CD4 counts, CD4 percentages, and viral load (VL) were examined at 6-monthly intervals. Various definitions of immunologic failure were examined to identify individuals with VLs>or=50, >or=500, >or=1000, or >or=5000 copies per milliliter at 6, 12, and 18 months after treatment initiation. One thousand sixty-three ART-naive persons initiated ART. The proportion of individuals with virologic failure ranged between 1.5% and 16.4% for each time point. The proportion with no increase in CD4 count from baseline did not differ between those with suppressed or unsuppressed VLs at 6, 18, and 24 months after ART initiation. No increase in CD4 cell counts at 6 months had a sensitivity of 0.04 [95% confidence interval (CI) 0.00 to 0.10] and a positive predictive value of 0.03 (95% CI 0.00 to 0.09) for identifying individuals with VL>or=500 copies per milliliter at 6 months. The best measure identified was an absolute CD4 cell count<125 cells per microliter at 21 months for predicting VL>or=500 copies per milliliter at 18 months which had a sensitivity of 0.13 (95% CI 0.01 to 0.21) and a positive predictive value of 0.29 (95% CI 0.10 to 0.44). CD4 cell count monitoring does not accurately identify individuals with virologic failure among patients taking ART.

Poor adherence to HIV monitoring and treatment guidelines for HIV-infected injection drug users

There is growing concern about access to HIV/AIDS care among injection drug users (IDUs). We examined rates of CD4 cell count monitoring and correlates among HIV-infected IDUs. This prospective observational cohort study of 460 community-recruited HIV-infected IDUs was situated in a Canadian city where all medical care is provided free of charge. Over a median follow-up period of 76 months, we evaluated factors associated with CD4 cell count monitoring through a linkage with a centralized CD4 registry. Overall, <5% of IDUs had CD4 monitoring consistent with local therapeutic guidelines. In multivariate analyses, after adjustment for being on antiretroviral therapy [odds ratio (OR) 2.21, 95% confidence interval (CI) 1.84-2.70, P<0.001] female gender (OR 0.71, 95% CI 0.57-0.89, P=0.003), non-White ethnicity (OR 0.75, 95% CI 0.60-0.94, P=0.014), use of methadone maintenance therapy (OR 1.66, 95% CI 1.42-1.94, P<0.001) and daily heroin use (OR 0.72, 95% CI 0.61-0.85, P<0.001) were independently associated with CD4 monitoring. Strategies to improve CD4 surveillance among IDUs are critically important, particularly for female and non-White IDUs. Expanded treatment for heroin dependence appears to have the greatest potential for improved care.

Outcomes from monitoring of patients on antiretroviral therapy in resource-limited settings with viral load, CD4 cell count, or clinical observation alone: a computer simulation model

In lower-income countries, WHO recommends a population-based approach to antiretroviral treatment with standardised regimens and clinical decision making based on clinical status and, where available CD4 cell count, rather than viral load. Our aim was to study the potential consequences of such monitoring strategies, especially in terms of survival and resistance development. A validated computer simulation model of HIV infection and the effect of antiretroviral therapy was used to compare survival, use of second-line regimens, and development of resistance that result from different strategies-based on viral load, CD4 cell count, or clinical observation alone-for determining when to switch people starting antiretroviral treatment with the WHO-recommended first-line regimen of stavudine, lamivudine, and nevirapine to second-line antiretroviral treatment. Over 5 years, the predicted proportion of potential life-years survived was 83% with viral load monitoring (switch when viral load >500 copies per mL), 82% with CD4 cell count monitoring (switch at 50% drop from peak), and 82% with clinical monitoring (switch when two new WHO stage 3 events or a WHO stage 4 event occur). Corresponding values over 20 years were 67%, 64%, and 64%. Findings were robust to variations in model specification in extensive univariable and multivariable sensitivity analyses. Although survival was slightly longer with viral load monitoring, this strategy was not the most cost effective. For patients on the first-line regimen of stavudine, lamivudine, and nevirapine the benefits of viral load or CD4 cell count monitoring over clinical monitoring alone are modest. Development of cheap and robust versions of these assays is important, but widening access to antiretrovirals-with or without laboratory monitoring-is currently the highest priority.

Lessons Learned from Use of Highly Active Antiretroviral Therapy in Africa

Because antiretrovirals are becoming increasingly available in developing countries, we reviewed the findings of studies that have documented highly active antiretroviral therapy (HAART) use in Africa to identify lessons learned. With the World Health Organization (WHO) guidelines used as a frame of reference, we assessed the feasibility of implementing such programs in Africa. Moreover, clinical and laboratory outcomes were compiled to determine the effectiveness of HAART programs. We searched academic databases and recent conference abstracts for studies, and we included all studies that documented patients receiving HAART in Africa. In particular, we examined studies for such program features as type of regimen and frequency of monitoring, in addition to evaluations of patient outcomes. Twenty-eight articles and abstracts involving studies from 14 African countries were reviewed. Overall, 6052 patients (96.4%) were receiving HAART, mainly consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) and 1 nonnucleoside reverse-transcriptase inhibitor. All studies reported an increase in mean and median CD4 cell counts, and a median of 73% of patients achieved undetectable viral loads by the end of the study period. Monitoring of CD4 cell count and viral load at 6-month intervals was completed by all studies. The median weight gained was 5.0 kg, and the median mortality rate was 7.4% (range, 0%-27%). Six studies reported that 68%-99% of patients took >95% of medications. Five studies measured drug resistance; most cases of resistance involved NRTIs. Many studies reported positive health outcomes, including high levels of treatment adherence that were comparable to those of industrialized countries. Regimens and monitoring means based on WHO guidelines were implemented--and at times, exceeded--in all studies reviewed. We found compelling evidence that HAART can be feasibly administered in resource-limited settings.

Optimal Frequency of Cd4 Cell Count and HIV Rna Monitoring Prior to Initiation of Antiretroviral Therapy in HIV-Infected Patients

Guidelines regarding the frequency of CD4 cell count and HIV RNA monitoring in HIV-infected patients vary, with recommended strategies ranging from every 2 to every 6 months. To determine optimal CD4 cell count and HIV RNA monitoring frequency in HIV-infected patients prior to antiretroviral therapy initiation. Cost-effectiveness (CE) analysis using an HIV simulation model incorporating CD4 cell count and HIV RNA as immunological and virological predictors of clinical outcomes. Hypothetical clinical setting. Simulated cohort based on initial clinical presentation of HIV-infected patients in the US. CD4 cell count and HIV RNA monitoring at frequencies ranging from every 2 to 24 months prior to antiretroviral initiation, as well as accelerated monitoring frequencies as CD4 cell counts approach a specified treatment threshold. Life expectancy, quality-adjusted life expectancy and costs. For patients presenting with median CD4 cell count 546/mm3 and median HIV RNA 4.8 log10 copies/ml, incremental CE ratios ranged from US$37800/quality-adjusted life year (QALY) gained for a constant testing frequency of every 18 months compared with every 24 months, to US$303300/QALY gained for a constant testing frequency of every 2 months compared with every 4 months when starting treatment at a CD4 cell count of 350/mm3. Monitoring every 12 months until a warning CD4 cell count threshold of 450/mm3 followed by every 3 months until 350/mm3 had an incremental CE ratio of US$74700/QALY gained. When starting antiretroviral therapy at CD4 cell count 200/mm3, monitoring every 12 months until 300/mm3 followed by every 2 months until treatment initiation yielded an incremental CE ratio of US$52200/QALY gained compared with the next best strategy. Increasing monitoring frequency as CD4 cell counts approached a treatment threshold yielded greater incremental clinical benefit for less cost than strategies using a constant frequency. Monitoring HIV-infected patients every 12 months until 100 CD4 cells/mm3 prior to a specified treatment threshold followed by more frequent monitoring every 2 or 3 months until antiretroviral therapy initiation is both more effective and cost-effective than the current standard of care.

CD4 cell count changes in individuals with counts above 500 cells/mm3 and viral loads below 50 copies/ml on antiretroviral therapy

We prospectively followed 166 individuals on antiretroviral therapy with viral loads less than 50 copies/ml and CD4 cell counts greater than 500 cells/mm 3 to ascertain CD4 cell count changes while the viral load remained below 50 copies/ ml. On average, CD4 cell counts remained stable and high. Only five patients experienced a decline to below 350 cells/mm 3 , and these were typically isolated low values with CD4 cell percentages remaining high. Our findings suggest that it may be possible to reduce the frequency of CD4 cell count monitoring in individuals with a value greater than 500 cells/mm 3 so long as regular viral load monitoring indicates a value less than 50 copies/ml.

2.3 HIV and intermediate immune deficiency

Intermediate immune deficiency is defined by a CD4 cell count between 500/microL and 200/microL. This phase is one of increasing therapeutic intervention, mostly for minor infections of skin and mucous membranes and mostly manageable within general practice. Most people with HIV begin antiretroviral therapy during this phase. Regular monitoring of CD4 cell count is essential for making appropriate therapeutic decisions and for determining prognosis.