Haemoglobin recovery among HIV-1 infected patients on zidovudine-based antiretroviral therapy and other regimens in north-central Nigeria.
TL;DR: Although haemoglobin levels increased overall for patients on zidovudine-containing regimens, for those in the 10th and 90th percentiles haem oxygen levels trended downward over time, these results have implications for decisions regarding when to initiate, switch from or avoid the use of zidvudine.
Abstract: We conducted a study to assess trends in haemoglobin recovery among HIV-infected patients initiated on zidovudine-based combination antiretroviral therapy (cART) stratified by baseline haemoglobin level. Haemoglobin data from non-pregnant adult patients initiating cART in rural north-central Nigeria between June 2009 and May 2011 were analysed using a linear mixed effects model to assess the interaction between time, zidovudine-containing regimen and baseline haemoglobin level on the outcome of subsequent haemoglobin level. Best-fit curves were created for baseline haemoglobin in the 10th, 25th, 75th and 90th percentiles. We included 313 patients with 736 measures of haemoglobin in the analysis (239 on zidovudine and 74 on non-zidovudine-containing regimens). Median haemoglobin increased over time in both groups, with differences in haemoglobin response over time related to baseline haemoglobin levels and zidovudine use (p = 0.003). The groups of patients on zidovudine at the 10th and 90th percentiles had downward sloping curves while all other groups had upward trending haemoglobin levels. Although haemoglobin levels increased overall for patients on zidovudine-containing regimens, for those in the 10th and 90th percentiles haemoglobin levels trended downward over time. These results have implications for decisions regarding when to initiate, switch from or avoid the use of zidovudine.
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TL;DR: Among both men and women, HIV infection was a consistent risk factor for severity of anemia, though its relative effect was stronger on moderate-to-severe anemia.
Abstract: The global burden of anemia is large especially in sub-Saharan Africa, where HIV is common and lifestyles are changing rapidly with urbanization. The effects of these changes are unknown. Studies of anemia usually focus on pregnant women or children, among whom the burden is greatest. We describe prevalence and risk factors for anemia among rural and urban men and women of all ages in Malawi. We analyzed data from a population-wide cross-sectional survey of adults conducted in two sites, Karonga (rural) and Lilongwe (urban), commencing in May 2013. We used multinomial logistic regression models, stratified by sex to identify risk factors for mild and moderate-to-severe anemia. Anemia prevalence was assessed among 8,926 men (age range 18–100 years) and 14,978 women (age range: 18–103 years). Weighted prevalence levels for all, mild, and moderate-to-severe anemia were 8.2, 6.7 and 1.2% in rural men; 19.4, 12.0 and 7.4% in rural women; 5.9, 5.1 and 0.8% in urban men; and 23.4, 13.6 and 10.1% in urban women. Among women, the odds of anemia were higher among urban residents and those with higher socioeconomic status. Increasing age was associated with higher anemia prevalence in men. Among both men and women, HIV infection was a consistent risk factor for severity of anemia, though its relative effect was stronger on moderate-to-severe anemia. The drivers of anemia in this population are complex, include both socioeconomic and biological factors and are affecting men and women differently. The associations with urban lifestyle and HIV indicate opportunities for targeted intervention.
65 citations
Cites background from "Haemoglobin recovery among HIV-1 in..."
...Conversely, use of certain ART medications (Zidovudine) may be associated with increased risk of anemia, through myelosuppression [47, 49]....
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TL;DR: Although anaemia was very common among ART-naive patients, the anaemia resolved during the first year of ART in a large majority of patients regardless of TB status without routine use of additional interventions, however, approximately one-quarter of patients remained anaemic after one year ofART and may require additional investigations and/or interventions.
Abstract: Anaemia is frequently associated with both HIV-infection and HIV-related tuberculosis (TB) in antiretroviral therapy (ART)-naive patients in sub-Saharan Africa and is strongly associated with poor prognosis. However, the effect of ART on the resolution of anaemia in patient cohorts with a high prevalence and incidence of tuberculosis is incompletely defined and the impact of TB episodes on haemoglobin recovery has not previously been reported. We therefore examined these issues using data from a well-characterised cohort of patients initiating ART in South Africa. Prospectively collected clinical and haematological data were retrospectively analysed from patients receiving ART in a South African township ART service. TB diagnoses and time-updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded. Anaemia severity was classified according to WHO criteria. Multivariable logistic regression analysis was used to determine factors independently associated with anaemia after 12 months of ART. Of 1,140 patients with baseline haemoglobin levels, 814 were alive in care and had repeat values available after 12 months of ART. The majority of patients were female (73%), the median CD4 count was 104 cells/uL and 30.5% had a TB diagnosis in the first year of ART. At baseline, anaemia (any severity) was present in 574 (70.5%) patients and was moderate/severe in 346 (42.5%). After 12 months of ART, 218 (26.8%) patients had anaemia of any severity and just 67 (8.2%) patients had moderate/severe anaemia. Independent predictors of anaemia after 12 months of ART included greater severity of anaemia at baseline, time-updated erythrocyte microcytosis and receipt of an AZT-containing regimen. In contrast, prevalent and/or incident TB, gender and baseline and time-updated CD4 cell count and viral load measurements were not independent predictors. Although anaemia was very common among ART-naive patients, the anaemia resolved during the first year of ART in a large majority of patients regardless of TB status without routine use of additional interventions. However, approximately one-quarter of patients remained anaemic after one year of ART and may require additional investigations and/or interventions.
40 citations
Cites background or result from "Haemoglobin recovery among HIV-1 in..."
...Haemoglobin recovery among those exposed to an AZT-containing regimen was similar to those without exposure to AZT, consistent with other African-based studies [41,45,46,55]....
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...Our findings are in agreement with several other studies from both lowand high-resource settings that demonstrate a strong, consistent benefit of ART for HIV-related anaemia [1,14,17,35,37-39,41,44,45,54,55]....
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...In subSaharan Africa where the prevalence of HIV-related anaemia remains high, previous studies have shown that ART is likely associated with significant haemoglobin recovery [1,2,40-46]....
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TL;DR: Newly admitted HIV-infected adults had a high prevalence of severe or life-threatening anemia and blood transfusions were frequently required, however, after adjustment for confounders, blood transfusion did not confer an increased mortality risk.
Abstract: Background. Morbidity and mortality remain high among hospitalized patients infected with human immunodeficiency virus (HIV) in sub-Saharan Africa despite widespread availability of antiretroviral therapy. Severe anemia is likely one important driver, and some evidence suggests that blood transfusions may accelerate HIV progression and paradoxically increase short-term mortality. We investigated the relationship between anemia, blood transfusions, and mortality in a South African district hospital. Methods. Unselected consecutive HIV-infected adults requiring acute medical admission to a Cape Town township district hospital were recruited. Admission hemoglobin concentrations were used to classify anemia severity according to World Health Organization/AIDS Clinical Trials Group criteria. Vital status was determined at 90 days, and Cox regression analyses were used to determine independent predictors of mortality. Results. Of 585 HIV-infected patients enrolled, 578 (98.8%) were included in the analysis. Anemia was detected in 84.8% of patients and was severe (hemoglobin, 6.5-7.9 g/dL) or life-threatening (hemoglobin, <6.5 g/dL) in 17.3% and 13.3%, respectively. Within 90 days of the date of admission, 13.5% (n = 78) patients received at least 1 blood transfusion with red cell concentrate and 77 (13.3%) patients died. In univariable analysis, baseline hemoglobin and receipt of blood transfusion were associated with increased mortality risk. However, in multivariable analysis, neither hemoglobin nor receipt of a blood transfusion were independently associated with greater mortality risk. Acquired immune deficiency syndrome-defining illnesses other than tuberculosis and impaired renal function independently predicted mortality. Conclusions. Newly admitted HIV-infected adults had a high prevalence of severe or life-threatening anemia and blood transfusions were frequently required. However, after adjustment for confounders, blood transfusions did not confer an increased mortality risk.
14 citations
Cites background or result from "Haemoglobin recovery among HIV-1 in..."
...Previous studies in sub-Saharan Africa have also reported a similarly high prevalence of HIV-related anemia, sometimes approaching as high as 90% [3, 5, 6, 32]; however, such estimates are largely derived among ART-naive, ambulatory outpatients....
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...Antiretroviral therapy is strongly associated with the resolution of anemia in a majority of patients [3, 5, 6, 13, 14], and a previous study found that ART was associated with decreased blood transfusion requirements [40]....
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...ART is associated with substantial hemoglobin recovery, resulting in resolution of anemia in a majority of HIV-infected African patients without additional specific hematological interventions [3, 5, 6, 13, 14]....
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TL;DR: HIV-infected women in the prevention of mother-to-child HIV transmission program were more likely to bring in their infants for EID if they were enrolled in a more urbanized clinic location, and if they presented during an earlier phase of the program.
Abstract: Despite efforts to halt mother-to-child transmission of HIV, incident pediatric HIV infections continue to occur, especially in sub-Saharan Africa (SSA). In 2011, 90% of the 390,000 new pediatric HIV cases worldwide were in SSA, and nearly all infections were acquired via vertical transmission.1 The early initiation of HIV-infected infants on antiretroviral therapy (ART) is associated with better clinical and immunological outcomes and improved survival.3-7 Yet early ART initiation in children is only achievable if HIV-infected infants are identified via Early Infant Diagnosis (EID) testing. This task is proving daunting; in 2012, only a third of HIV-exposed infants across reporting countries underwent EID testing.2 EID coverage was even worse in SSA, where 6 of 31 countries reported EID testing rates below 10%, resulting in millions of undiagnosed HIV-exposed infants.2,8 ART coverage among HIV-infected children in 2012 was also approximately half the coverage for adults (34% vs. 64%, respectively).2
Nigeria has the second-largest number of persons living with HIV in the world and is a major contributor to the global epidemic of pediatric HIV/AIDS. Despite an estimated 59,000 children being newly infected with HIV in Nigeria in 2012 alone,2 EID service uptake remains extremely poor.9 Nigeria national guidelines recommend EID testing at 6 weeks postpartum, but HIV-1 DNA PCR testing for EID was performed in only 4% of eligible infants by 2 months of age in 2010.10 ART coverage among HIV-infected Nigerian children in 2010 was also a paltry 12%.2 Low uptake of EID may be due in part to low uptake of antenatal and postnatal care services by pregnant women,11 lack of service availability at rural clinical sites,12 as well as social and educational barriers that limit women’s ability to access these services.13-15 Other contributory factors include: limited number of centralized laboratories with requisite capacity to perform DNA PCR testing, long turn-around times, stock-outs of reagents and consumables, and logistical challenges with getting results back to facilities/healthcare providers. One of the goals of Nigeria’s national PMTCT scale-up plan is to provide at least 90% of all HIV-exposed infants with access to EID services by 2015.16 Accomplishing this goal will require changes to health care delivery that adequately address the mentioned barriers and contributing factors impeding EID uptake in Nigeria.
The Vanderbilt Institute for Global Health (VIGH) was funded from 2008-2013 through the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) to assist in provision of comprehensive HIV/AIDS services in the Federal Capital Territory (FCT, Abuja) and rural parts of Kwara and Niger states in north-central Nigeria. Whereas several studies describing experiences with implementation of EID programs in SSA exist,17-21 there is a dearth of peer-reviewed reports from Nigeria, one of the 22 “Global Plan” focus countries.22 The aim of this study is to describe the characteristics of pregnant women enrolled in HIV care and treatment in VIGH-supported clinics in rural north central Nigeria, characterize those women who bring their HIV-exposed infants for EID, and to determine the maternal correlates associated with initiation of EID. Lessons learnt from rural Nigeria can help inform EID programming, family and community engagement, and quality improvement efforts in similarly challenging environments.
9 citations
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...Gawu Babangida Rural Hospital 82 (23) 92 (26) 174 (24)...
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01 Jan 2016
TL;DR: It is found that moderate or severe anaemia was highly predictive of both prevalent and incident tuberculosis among ambulatory outpatients as well as hospitalised in-patients in South Africa and was also a very strong independent predictor of mortality.
Abstract: Tuberculosis remains the leading cause of death among people living with HIV in sub-Saharan Africa and worldwide. The clinical presentation in such patients is often so non-specific that much tuberculosis remains unsuspected, undiagnosed and is therefore untreated prior to death. Anaemia is one of the most common complications of both HIV and tuberculosis, and is associated with substantial morbidity and mortality. Haemoglobin levels may be a useful biomarker in patients with HIV-associated tuberculosis and anaemia may have predictive value that is under-utilized as an important entry point into the tuberculosis diagnostic algorithm. This thesis found that moderate or severe anaemia was highly predictive of both prevalent and incident tuberculosis among ambulatory outpatients as well as hospitalised in-patients in South Africa and was also a very strong independent predictor of mortality. Therefore, in high tuberculosis incidence areas in sub-Saharan Africa, all HIV-infected patients with moderate or severe anaemia should be suspected of having tuberculosis and be microbiologically tested for tuberculosis using rapid diagnostic assays regardless of symptomatology. Because anaemia of chronic disease, a process driven by elevated hepcidin levels, is the most common mechanism underlying anaemia in these patients, the majority can be expected to have resolution of anaemia with antiretroviral therapy and anti-tuberculosis therapy alone. The impact of such screening and treatment strategies on HIV-associated tuberculosis in sub-Saharan is not yet known and must be evaluated in future research.
4 citations
Cites background or result from "Haemoglobin recovery among HIV-1 in..."
...Previous studies in sub-Saharan Africa have also reported a similarly high prevalence of HIV-related anemia, sometimes approaching as high as 90% [3, 5, 6, 32]; however, such estimates are largely derived among ART-naive, ambulatory outpatients....
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...Antiretroviral therapy is strongly associated with the resolution of anemia in a majority of patients [3, 5, 6, 13, 14], and a previous study found that ART was associated with decreased blood transfusion requirements [40]....
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...ART is associated with substantial hemoglobin recovery, resulting in resolution of anemia in a majority of HIV-infected African patients without additional specific hematological interventions [3, 5, 6, 13, 14]....
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References
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TL;DR: In this article, a unified approach to fitting two-stage random-effects models, based on a combination of empirical Bayes and maximum likelihood estimation of model parameters and using the EM algorithm, is discussed.
Abstract: Models for the analysis of longitudinal data must recognize the relationship between serial observations on the same unit. Multivariate models with general covariance structure are often difficult to apply to highly unbalanced data, whereas two-stage random-effects models can be used easily. In two-stage models, the probability distributions for the response vectors of different individuals belong to a single family, but some random-effects parameters vary across individuals, with a distribution specified at the second stage. A general family of models is discussed, which includes both growth models and repeated-measures models as special cases. A unified approach to fitting these models, based on a combination of empirical Bayes and maximum likelihood estimation of model parameters and using the EM algorithm, is discussed. Two examples are taken from a current epidemiological study of the health effects of air pollution.
8,410 citations
22 Apr 2014
TL;DR: The generalized additive model (GA) as discussed by the authors is a generalization of the generalized linear model, which replaces the linear model with a sum of smooth functions in an iterative procedure called local scoring algorithm.
Abstract: Likelihood-based regression models such as the normal linear regression model and the linear logistic model, assume a linear (or some other parametric) form for the covariates $X_1, X_2, \cdots, X_p$. We introduce the class of generalized additive models which replaces the linear form $\sum \beta_jX_j$ by a sum of smooth functions $\sum s_j(X_j)$. The $s_j(\cdot)$'s are unspecified functions that are estimated using a scatterplot smoother, in an iterative procedure we call the local scoring algorithm. The technique is applicable to any likelihood-based regression model: the class of generalized linear models contains many of these. In this class the linear predictor $\eta = \Sigma \beta_jX_j$ is replaced by the additive predictor $\Sigma s_j(X_j)$; hence, the name generalized additive models. We illustrate the technique with binary response and survival data. In both cases, the method proves to be useful in uncovering nonlinear covariate effects. It has the advantage of being completely automatic, i.e., no "detective work" is needed on the part of the statistician. As a theoretical underpinning, the technique is viewed as an empirical method of maximizing the expected log likelihood, or equivalently, of minimizing the Kullback-Leibler distance to the true model.
5,700 citations
"Haemoglobin recovery among HIV-1 in..." refers methods in this paper
...To account for non-linearity, baseline haemoglobin and time were transformed using natural cubic splines with three knots.(16) Best fit curves depicting trajectories of haemoglobin were created for four strata of baseline haemoglobin: the 10th, 25th, 75th and 90th percentiles....
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TL;DR: It is demonstrated that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study.
Abstract: We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) manifested by Pneumocystis carinii pneumonia alone, or with advanced AIDS-related complex. The subjects were stratified according to numbers of T cells with CD4 surface markers and were randomly assigned to receive either 250 mg of AZT or placebo by mouth every four hours for a total of 24 weeks. One hundred forty-five subjects received AZT, and 137 received placebo. When the study was terminated, 27 subjects had completed 24 weeks of the study, 152 had completed 16 weeks, and the remainder had completed at least 8 weeks. Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT. The base-line Karnofsky performance score and weight increased significantly among AZT recipients (P less than 0.001). A statistically significant increase in the number of CD4 cells was noted in subjects receiving AZT (P less than 0.001). After 12 weeks, the number of CD4 cells declined to pretreatment values among AZT recipients with AIDS but not amonG AZT recipients with AIDS-related complex. Skin-test anergy was partially reversed in 29 percent of subjects receiving AZT, as compared with 9 percent of those receiving placebo (P less than 0.001). These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study.
3,062 citations
Journal Article•
TL;DR: Almost all of the persistent severe neutropenia disappeared after cotrimoxazole was stopped, suggesting an accentuated drug interaction between the two drugs in these sub-Saharan African individuals.
Abstract: Objective: Neutropenia is the most frequent side effect of cotrimoxazole in sub-Saharan Africa. We estimated the incidence of haematological disorders during the first 6 months of a zidovudine-containing highly active antiretroviral therapy (HAART) regimen in sub-Saharan African adults receiving cotrimoxazole. Methods: Prospective cohort study in Abidjan, with blood cell count measurement at baseline (HAART initiation), month 1, month 3 and month 6. Results: A total of 498 adults [baseline: 80% currently on cotrimoxazole prophylaxis; median CD4 count 237/mm 3 [interquartile range (IQR) 181;316]; median neutrophil count 1647/mm 3 (IQR 1221;2256); median haemoglobin 113 g/l (IQR 102;122)] started zidovudine (AZT)/lamivudine/efavirenz. During follow-up, 118 patients had a grade 3-4 neutropenia [(56.3/100 person-years (PY)], 23 had a grade 3-4 anaemia (9.6/100 PY) and no cases of grade 3-4 thrombocytopenia. Of the 118 patients with grade 3-4 neutropenia, 86 (73%) had to stop cotrimoxazole because neutropenia persisted, and one (<1%) had to stop AZT because of persistent neutropenia after cotrimoxazole was stopped (neutropenia-related HAART modification: 0.4/100 PY). Of the 23 patients with grade 3-4 anaemia, 11 had to stop AZT (anaemia-related HAART modification: 4.4/100 PY). In patients who stopped cotrimoxazole but not AZT, the median gain in neutrophils at 1 month was +540/mm 3 (IQR+150;+896). Conclusions: At baseline, most patients had a normal neutrophil count and 80% of them were already receiving cotrimoxazole. An unexpectedly high rate of grade 3-4 neutropenia occurred shortly after introduction of AZT. Almost all of the persistent severe neutropenia disappeared after cotrimoxazole was stopped. This suggests an accentuated drug interaction between the two drugs in these sub-Saharan African individuals. Grade 3-4 anaemia was much less frequent, but remained the first cause of AZT discontinuation.
126 citations
"Haemoglobin recovery among HIV-1 in..." refers result in this paper
...Our findings are consistent with a prior study in West Africa that found associations between the risk of grade 3 and 4 anaemia with low baseline haemoglobin levels.(17) For the patients starting ART at the highest levels of haemoglobin, a regression to the mean phenomenon is likely....
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Journal Article•
TL;DR: A higher incidence of grade 4 anaemia is observed in previously untreated symptomatic HIV-infected adults with CD4+ T-cells <200 cells/mm(3) initiating zidovudine-containing regimens in Africa than in studies from industrialized countries, which is likely to be due in part to population characteristics and inpart to a higher rate of concurrent HIV-related clinical events.
Abstract: The DART trial is funded by the UK Medical Research Council, the UK Department for
International Development, and the Rockefeller Foundation. First-line drugs are provided by
GlaxoSmithKline, Gilead and Boehringer Ingelheim.
76 citations
"Haemoglobin recovery among HIV-1 in..." refers result in this paper
...multicenter cohort study including sites in Sub-Saharan Africa, Asia-Pacific and Latin America found associations between initial therapy containing ZDV and anaemia.(6,7) Variability in findings is expected given that the studies had different structures and outcomes, with some analysing incident anaemia in patients with normal haemoglobin and others looking at changes in haemoglobin levels among anemic patients initiating ZDV-based regimens....
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