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1.  Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort 
Background
Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial.
Methods
To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated.
Results
CD4+ count at HAART initiation was ≤ 200 cells/mm3 for 23%, 201-349 for 31%, 350-499 for 27%, and ≥500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93-151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05).
Conclusions
Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible.
doi:10.1186/1742-6405-8-2
PMCID: PMC3037838  PMID: 21244701
2.  Outcomes of highly active antiretroviral therapy in the context of universal access to healthcare: the U.S. Military HIV Natural History Study 
Background
To examine the outcomes of highly-active antiretroviral therapy (HAART) for individuals with free access to healthcare, we evaluated 2327 patients in a cohort study composed of military personnel and beneficiaries with HIV infection who initiated HAART from 1996 to the end of 2007.
Methods
Outcomes analyzed were virologic suppression (VS) and failure (VF), CD4 count changes, AIDS and death. VF was defined as never suppressing or having at least one rebound event. Multivariate (MV) analyses stratified by the HAART initiation year (before or after 2000) were performed to identify risk factors associated with these outcomes.
Results
Among patients who started HAART after 2000, 81% had VS at 1 year (N = 1,759), 85% at 5 years (N = 1,061), and 82% at 8 years (N = 735). Five years post-HAART, the median CD4 increase was 247 cells/ml and 34% experienced VF. AIDS and mortality rates at 5 years were 2% and 0.3%, respectively. In a MV model adjusted for known risk factors associated with treatment response, being on active duty (versus retired) at HAART initiation was associated with a decreased risk of AIDS (HR = 0.6, 95% CI 0.4-1.0) and mortality (0.6, 0.3-0.9), an increased probability of CD4 increase ≥ 50% (1.2, 1.0-1.4), but was not significant for VF.
Conclusions
In this observational cohort, VS rates approach those described in clinical trials. Initiating HAART on active duty was associated with even better outcomes. These findings support the notion that free access to healthcare likely improves the response to HAART thereby reducing HIV-related morbidity and mortality.
doi:10.1186/1742-6405-7-14
PMCID: PMC2894737  PMID: 20507622
3.  A Frailty-Related Phenotype Before HAART Initiation as an Independent Risk Factor for AIDS or Death After HAART Among HIV-Infected Men 
Background.
In the general population, frailty, a late stage of the aging process, predicts mortality. We investigated whether manifesting a previously defined frailty-related phenotype (FRP) before initiating highly active antiretroviral therapy (HAART) affects the likelihood of developing clinical AIDS or mortality after HAART initiation.
Methods.
Among 596 HIV-infected men in the Multicenter AIDS Cohort Study whose date of HAART initiation was known within ±6 months and who had an assessable FRP status within 3 years before HAART, survival analyses were performed to assess the effect of FRP manifestation on clinical AIDS or death after HAART.
Results.
In men free of AIDS before HAART, AIDS or death after HAART occurred in 13/36 (36%) men who exhibited the FRP before HAART but only in 69/436 (16%) men who did not (hazard ratio = 2.6; 95% confidence interval = 1.4–4.6; p < .01). After adjusting for age, ethnicity, education, nadir CD4+ T-cell count, peak HIV viral load, and hemoglobin in the 3 years before HAART, having the FRP at >25% of visits in the 3 years before HAART significantly predicted AIDS or death (adjusted hazard ratio = 3.8; 95% confidence interval = 1.9–7.9; p < .01). Results were unchanged when the analysis was restricted to the 335 AIDS-free men who were HAART responders, to the 124 men who had AIDS at HAART initiation, or to the subsets of men for whom indices of liver and kidney function could be taken into account.
Conclusion.
Having a persistent frailty-like phenotype before HAART initiation predicted a worse prognosis after HAART, independent of known risk factors.
doi:10.1093/gerona/glr097
PMCID: PMC3156632  PMID: 21719610
HIV; Aging; Frailty; HAART response; Survival analysis
4.  Timing of Antiretroviral Therapy Initiation and its Impact on Disease Progression in Perinatal Human Immunodeficiency Virus-1 Infection 
Objective
Treatment with highly active antiretroviral therapy (HAART) reduces overall perinatal HIV-1 related mortality. The impact of timing of HAART initiation on reduction of morbidity is not well-defined. We evaluated the association of timing of HAART initiation on progression to moderate or severe disease.
Methods
Retrospective, population-based study of 196 perinatally HIV-infected children followed from birth in northern California from 1988 to 2009.
Results
Of 196 children, 58% received HAART and were followed for a median of 6.2 years after HAART initiation. HAART use was associated with improved survival to age 5 years: 50% no HAART vs. 88% HAART, p<0.0001. However, the advantage of initial HAART over mono or dual therapy transitioning to HAART was small and not statistically significant (p=0.23). Starting HAART before the development of moderate or severe disease delayed the median age of diagnosis of moderate disease from 0.4 years (IQR [0.3–0.8]) without HAART to 3.0 years ([IQR 1.9–5.8], p<.0001) with HAART. HAART initiation after progression to moderate or severe disease was associated with decreased progression to severe disease or death, respectively (moderate to severe: 8% (3/36) HAART vs. 84% (70/83) no HAART, p<0.0001; severe to death: 9% (6/68) HAART vs. 73% (49/67) no HAART, p<0.0001).
Conclusion
In perinatal HIV infection, HAART is associated with delayed progression and reduced mortality regardless of disease severity at HAART initiation. This finding reinforces U.S. guidelines regarding HAART initiation at>1 year of age if children present with most clinical category B diagnoses, regardless of CD4 measurements or plasma HIV RNA level.
doi:10.1097/INF.0b013e31823515a2
PMCID: PMC3252403  PMID: 21979798
perinatal; HIV-1; highly active antiretroviral therapy (HAART); timing of onset
5.  Antiretroviral therapy at a district hospital in Ethiopia prevents death and tuberculosis in a cohort of HIV patients 
Background
Although highly active antiretroviral therapy (HAART) reduces mortality in the developed world, it remains undocumented in resource-poor settings. We assessed the effect of HAART on patient mortality and tuberculosis incidence rate under routine clinical care conditions in Ethiopia. The objective of this study was to assess the effect of HAART on patient mortality and tuberculosis incidence rate under routine clinical care conditions in a resource-limited setting in south Ethiopia. Starting in January 2003, we followed all consecutive adult HIV infected patients who visited the HIV clinic. Since August 2003, we treated patients with HAART. Only basic laboratory services were available.
Results
We followed 185 patients in the pre-HAART cohort and 180 patients in the HAART cohort. The mortality rate was 15.4 per 100 person-years of observation (PYO) in the HAART group and tuberculosis incidence rate was 3.7 per 100 PYO. In the pre-HAART group, the mortality rate was 58.1 per 100 PYO and the tuberculosis incidence rate was 11.1 per 100 PYO. HAART resulted in a 65% decline in mortality (adjusted hazard ratio [95%CI] = 0.35 [0.19–0.63]; P < 0.001). Tuberculosis incidence rate was lower in the HAART group (adjusted hazard ratio [95%CI] = 0.11 [0.03–0.48]; P < 0.01). Most of the deaths occurred during the first three months of treatment.
Conclusion
HAART improved survival and decreased tuberculosis incidence to a level similar to that achieved in the developed countries during the early years of HAART. However, both the mortality and the tuberculosis incidence rate were much higher in terms of absolute figures in this resource-limited setting. Attention should be paid to the early weeks of treatment when mortality is high. The high tuberculosis incidence rate, when coupled with the improved survival, may lead to increased tuberculosis transmission. This highlights the need for strengthening tuberculosis prevention efforts with the scale-up of treatment programmes
doi:10.1186/1742-6405-3-10
PMCID: PMC1475602  PMID: 16600050
6.  The Impact of HAART on Cardiomyopathy among Children and Adolescents Perinatally Infected with HIV-1 
AIDS (London, England)  2012;26(16):2027-2037.
Objective
Previous studies of cardiomyopathy among children perinatally infected with HIV were conducted before the routine use of highly active antiretroviral therapy (HAART). Nucleoside analogues (NRTIs), the backbone of HAART, have been associated with mitochondrial toxicity, which can lead to cardiomyopathy. We evaluated the association of HAART and specific NRTIs associated with mitochondrial toxicity, on development of cardiomyopathy among perinatally HIV-infected children.
Design
3,035 perinatally HIV-infected children enrolled in a US-based multicenter prospective cohort study, were followed for cardiomyopathy, defined as a clinical diagnosis or initiation of digoxin, from 1993–2007.
Methods
Cox models were used to estimate the effects of HAART and NRTIs on cardiomyopathy, identify predictors of cardiomyopathy among HAART users, and estimate the association between development of cardiomyopathy and mortality.
Results
99 cases of cardiomyopathy were identified over follow-up (incidence rate: 5.6 cases per 1,000 person-years) at a median age of 9.4 years. HAART was associated with a 50% lower incidence of cardiomyopathy compared to no HAART use (95% confidence interval: 20%, 70%). Zalcitabine (ddC) use, however, was associated with an 80% higher incidence of cardiomyopathy. Among HAART users, older age at HAART initiation, ddC use before HAART initiation, initiating a HAART regimen containing zidovudine (ZDV), and a nadir CD4<15% were independently associated with a higher rate of cardiomyopathy. Cardiomyopathy was associated with a 6-fold higher mortality rate.
Conclusions
HAART has dramatically decreased the incidence of cardiomyopathy among perinatally HIV-infected children. However, they remain at increased risk for cardiomyopathy and ongoing ZDV exposure may increase this risk.
doi:10.1097/QAD.0b013e3283578bfa
PMCID: PMC3513344  PMID: 22781228
cardiomyopathy; HAART; mortality; perinatally HIV-infected children; zidovudine
7.  Good adherence to HAART and improved survival in a community HIV/AIDS treatment and care programme: the experience of The AIDS Support Organization (TASO), Kampala, Uganda 
Background
Poor adherence to highly active antiretroviral therapy (HAART) may result in treatment failure and death. Most reports of the effect of adherence to HAART on mortality come from studies where special efforts are made to provide HAART under ideal conditions. However, there are few reports of the impact of non-adherence to HAART on mortality from community HIV/AIDS treatment and care programmes in developing countries. We therefore conducted a study to assess the effect of adherence to HAART on survival in The AIDS Support Organization (TASO) community HAART programme in Kampala, Uganda.
Methods
The study was a retrospective cohort of 897 patients who initiated HAART at TASO clinic, Kampala, between May 2004 and December 2006. A total of 7,856 adherence assessments were performed on the data. Adherence was assessed using a combination of self-report and pill count methods. Patients who took ≤ 95% of their regimens were classified as non-adherent. The data was stratified at a CD4 count of 50 cells/mm3. Kaplan Meier curves and Cox proportional hazards regression models were used in the analysis.
Results
A total of 701 (78.2%) patients had a mean adherence to ART of > 95%. The crude death rate was 12.2 deaths per 100 patient-years, with a rate of 42.5 deaths per 100 patient-years for non-adherent patients and 6.1 deaths per 100 patient-years for adherent patients. Non-adherence to ART was significantly associated with mortality. Patients with a CD4 count of less than 50 cells/mm3 had a higher mortality (HR = 4.3; 95% CI: 2.22–5.56) compared to patients with a CD4 count equal to or greater than 50 cells/mm3 (HR = 2.4; 95% CI: 1.79–2.38).
Conclusion
Our study showed that good adherence and improved survival are feasible in community HIV/AIDS programmes such as that of TASO, Uganda. However, there is need to support community HAART programmes to overcome the challenges of funding to provide sustainable supplies particularly of antiretroviral drugs; provision of high quality clinical and laboratory support; and achieving a balance between expansion and quality of services. Measures for the early identification and treatment of HIV infected people including home-based VCT and HAART should be strengthened.
doi:10.1186/1472-6963-8-241
PMCID: PMC2606686  PMID: 19021908
8.  Antiretroviral treatment and quality of life in Africans living with HIV: 12-month follow-up in Burkina Faso 
Introduction
The scale-up of highly active antiretroviral therapy (HAART) has led to a significant improvement in survival of the HIV-positive patient but its effects on health-related quality of life (HRQOL) are less known and context-dependent. Our aim was to assess the temporal changes and factors associated with HRQOL among HIV-positive adults initiating HAART in Burkina Faso.
Methods
HIV-positive people initiating HAART were prospectively included and followed over a one-year period in three HIV clinics of Ouagadougou. HRQOL was assessed at baseline and at each follow-up visit using physical (PHS) and mental (MHS) summary scores derived from the Medical Outcome Study 36-Item short-form health survey (MOS SF-36) questionnaire. Toxicity related to HAART modification and self-reported symptoms were recorded during follow-up visits. Determinants associated with baseline and changes in both scores over a one-year period were assessed using a mixed linear model.
Results
A total of 344 patients were included. Their median age at baseline was 37 years [interquartile range (IQR) 30–44] and their median CD4 count was 181 cells/mm3 (IQR 97–269). The mean [standard deviation (SD)] PHS score increased from 45.4 (11.1) at baseline to 60.0 (3.1) at 12 months (p<10−4) and the mean (SD) MHS score from 42.2 (8.7) to 43.9 (3.4) (p<10−2). After one year of treatment, patients that experienced on average two symptoms during follow-up presented with significantly lower PHS (63.9) and MHS (43.8) scores compared to patients that presented no symptoms with PHS and MHS of 68.2 (p<10−4) and 45.3 (p<10−3), respectively.
Discussion
The use of HAART was associated with a significant increase in both physical and mental aspects of the HRQOL over a 12-month period in this urban African population. Perceived symptoms experienced during follow-up visits were associated with a significant impairment in HRQOL. The appropriate and timely management of reported symptoms during the follow-up of HAART-treated patients is a key component to restore HRQOL.
doi:10.7448/IAS.16.1.18867
PMCID: PMC3871830  PMID: 24369739
quality of life; HIV/AIDS; antiretroviral treatment; Burkina Faso; sub-Saharan Africa
9.  Hospitalization risk following initiation of highly active antiretroviral therapy 
HIV medicine  2009;11(5):289-298.
Objectives
While highly active antiretroviral therapy (HAART) decreases long-term morbidity and mortality, its short-term effect on hospitalization rates is unknown. The primary objective of this study was to determine hospitalization rates over time in the year after HAART initiation for virological responders and nonresponders.
Methods
Hospitalizations among 1327 HAART-naïve subjects in an urban HIV clinic in 1997–2007 were examined before and after HAART initiation. Hospitalization rates were stratified by virological responders (≥ 1 log10 decrease in HIV-1 RNA within 6 months after HAART initiation) and nonresponders. Causes were determined through International Classification of Diseases, 9th Revision (ICD-9) codes and chart review. Multivariate negative binomial regression was used to assess factors associated with hospitalization.
Results
During the first 45 days after HAART initiation, the hospitalization rate of responders was similar to their pre-HAART baseline rate [75.1 vs. 78.8/100 person-years (PY)] and to the hospitalization rate of nonresponders during the first 45 days (79.4/100 PY). The hospitalization rate of responders fell significantly between 45 and 90 days after HAART initiation and reached a plateau at approximately 45/100 PY from 91 to 365 days after HAART initiation. Significant decreases were seen in hospitalizations for opportunistic and nonopportunistic infections.
Conclusions
The first substantial clinical benefit from HAART may be realized by 90 days after HAART initiation; providers should keep close vigilance at least until this time.
doi:10.1111/j.1468-1293.2009.00776.x
PMCID: PMC3077939  PMID: 20002778
AIDS-defining illness; antiretroviral therapy; healthcare utilization; hospitalization; immune reconstitution
10.  Is Antiretroviral Therapy Causing Long-Term Liver Damage? A Comparative Analysis of HIV-Mono-Infected and HIV/Hepatitis C Co-Infected Cohorts 
PLoS ONE  2009;4(2):e4517.
The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV/HCV co-infected patients, followed between January 1991 and July 2005 at a university-based HIV clinic, we investigated the relationship between cumulative HAART exposure and hepatic fibrosis, as measured by the aspartate aminotransferase-to-platelet ratio index (APRI). We used a novel methodological approach to estimate the dose-response relationship of the effect of HAART exposure on APRI. HAART was associated with increasing APRI over time in HIV/HCV co-infected patients suggesting that they may be experiencing cumulative hepatotoxicity from antiretrovirals. The estimated median change (95% confidence interval) in APRI per one year of HAART intake was of −0.46% (−1.61% to 0.71%) in HIV mono-infected compared to 2.54% (−1.77% to 7.03%) in HIV/HCV co-infected patients. Similar results were found when the direct effect of HAART intake since the last visit was estimated on the change in APRI. HAART use associated is with increased APRI in patients with HIV/HCV co-infection. Therefore treatment for HCV infection may be required to slow the growing epidemic of end-stage liver disease in this population.
doi:10.1371/journal.pone.0004517
PMCID: PMC2637977  PMID: 19223976
11.  Overestimates of Survival after HAART: Implications for Global Scale-Up Efforts 
PLoS ONE  2008;3(3):e1725.
Background
Monitoring the effectiveness of global antiretroviral therapy scale-up efforts in resource-limited settings is a global health priority, but is complicated by high rates of losses to follow-up after treatment initiation. Determining definitive outcomes of these lost patients, and the effects of losses to follow-up on estimates of survival and risk factors for death after HAART, are key to monitoring the effectiveness of global HAART scale-up efforts.
Methodology/Principal Findings
A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswana's National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [1-year Kaplan Meier survival estimate 0.92 (95% confidence interval, 0.88–0.94 before tracing and 0.83 (95% confidence interval, 0.79–0.86) after tracing, log rank P<0.001]. In addition, a significantly increased risk of death after HAART among men [adjusted hazard ratio 1.74 (95% confidence interval, 1.05–2.87)] would have been missed had patients not been traced [adjusted hazard ratio 1.41 (95% confidence interval, 0.65–3.05)].
Conclusions/Significance
Due to high rates of death among patients lost to follow-up after HAART, survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced. Patient tracing and uniform reporting of outcomes after HAART are needed to enable accurate monitoring of global HAART scale-up efforts.
doi:10.1371/journal.pone.0001725
PMCID: PMC2254493  PMID: 18320045
12.  Risk Factors for Tuberculosis After Highly Active Antiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening 
The Journal of Infectious Diseases  2011;204(6):893-901.
Background. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts.
Methods. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995–August 2009. Parametric survival models identified factors associated with tuberculosis occurrence.
Results. Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131–333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk.
Conclusions. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm3 or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.
doi:10.1093/infdis/jir421
PMCID: PMC3156918  PMID: 21849286
13.  Younger age at HAART initiation is associated with more rapid growth reconstitution 
AIDS (London, England)  2011;25(3):345-355.
Objectives
Patterns of growth following highly active antiretroviral therapy (HAART) administration among children are not well defined. The objective of this study was to determine rates and predictors of growth reconstitution among children on HAART.
Methods
A study was conducted among HIV-1-infected children initiating HAART at an HIV treatment clinic in Kenya. Kaplan–Meier survival curves and Cox proportional hazards regression models compared catch-up growth (Z-score ≥0) at 12 months post-HAART. Multivariate linear mixed-effects models determined rates and predictors of growth following HAART.
Results
One hundred and seventy-three HIV-1-infected children initiated HAART with a median age of 4.7 years [interquartile range (IQR) 2.4, 7.0]. At baseline, children below 3 years had lower weight-for-age (WAZ) and weight-for-height (WHZ) Z-scores than children 3–5 and 6–10 years (WAZ: P = 0.03; WHZ: P = 0.006). Adjusting for baseline growth, children below 3 years were two to three-fold more likely to attain population age-norms (Z-score = 0) than 6–10 years (WAZ: P = 0.055; WHZ: P = 0.005) at 12 months post-HAART. After adjustment, children below 3 years had higher increases in WAZ and WHZ following HAART than 6–10 years (WAZ: P = 0.006; WHZ: P = 0.005). Children at WHO stage at least 3 at baseline experienced more rapid WHZ reconstitution (P = 0.002). Food supplementation while on HAART was associated with increased monthly gains in weight indices (WAZ: P = 0.001; WHZ: P = 0.005), and multivitamins were associated with greater increases in height (P < 0.01).
Conclusion
Following HAART initiation, younger children had more rapid catch-up to the population-average weight of their peers than older children, demonstrating growth benefit of earlier HAART. In addition to HAART, food supplementation and multivitamins may also accelerate growth reconstitution.
doi:10.1097/QAD.0b013e32834171db
PMCID: PMC3380084  PMID: 21102302
growth; HAART; HIV; nutritional supplementation; pediatrics; sub-Saharan Africa
14.  The Use of HAART Is Associated With Decreased Risk of Death During Initial Treatment of Cryptococcal Meningitis in Adults in Botswana 
Objective
The objective of this study was to evaluate outcomes among adults with a first episode of cryptococcal meningitis (CM), comparing those on highly active antiretroviral therapy (HAART) with those not on HAART.
Methods
We conducted a prospective cohort study among HIV-infected adults (aged 18 years and older) with a first episode of CM at the Princess Marina Hospital, in Gaborone, Botswana. The proportions surviving to discharge were compared. Logistic regression was used to evaluate the relationship between HAART use and risk of death in the hospital, adjusting for potential confounders.
Results
Ninety-two patients [median CD4 41 cells/mm3 (inter-quartile range 22–85)] were included, 26 of whom were on HAART at the time that they developed CM. The in-hospital mortality was lower among those on HAART {2 of 26 (8%) vs 14 of 66 (21%); odds ratio = 0.36 [95% confidence interval (CI) 0.09 to 1.49]}, and this result was statistically significant after adjustment for male sex and tuberculosis [adjusted odds ratio = 0.19 (95% CI 0.04 to 1.00)].
Conclusions
HAART use at the time of a first admission with CM is associated with decreased risk of death during the acute phase of disease. Reasons for this association should be explored.
doi:10.1097/QAI.0b013e318183181e
PMCID: PMC3704195  PMID: 18769344
cryptococcal meningitis; HAART; Africa; cohort study
15.  Admissions to intensive care unit of HIV-infected patients in the era of highly active antiretroviral therapy: etiology and prognostic factors 
Critical Care  2011;15(4):R202.
Introduction
Although access to highly active antiretroviral therapy (HAART) has prolonged survival and improved life quality, HIV-infected patients with severe immunosuppression or comorbidities may develop complications that require critical care support in intensive care units (ICU). This study aimed to describe the etiology and analyze the prognostic factors of HIV-infected Taiwanese patients in the HAART era.
Methods
Medical records of all HIV-infected adults who were admitted to ICU at a university hospital in Taiwan from 2001 to 2010 were reviewed to record information on patient demographics, receipt of HAART, and reason for ICU admission. Factors associated with hospital mortality were analyzed.
Results
During the 10-year study period, there were 145 ICU admissions for 135 patients, with respiratory failure being the most common cause (44.4%), followed by sepsis (33.3%) and neurological disease (11.9%). Receipt of HAART was not associated with survival. However, CD4 count was independently predictive of hospital mortality (adjusted odds ratio [AOR], per-10 cells/mm3 decrease, 1.036; 95% confidence interval [CI], 1.003 to 1.069). Admission diagnosis of sepsis was independently associated with hospital mortality (AOR, 2.91; 95% CI, 1.11 to 7.62). A hospital-to-ICU interval of more than 24 hours and serum albumin level (per 1-g/dl decrease) were associated with increased hospital mortality, but did not reach statistical significance in multivariable analysis.
Conclusions
Respiratory failure was the leading cause of ICU admissions among HIV-infected patients in Taiwan. Outcome during the ICU stay was associated with CD4 count and the diagnosis of sepsis, but was not associated with HAART in this study.
doi:10.1186/cc10419
PMCID: PMC3387644  PMID: 21871086
16.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
Background
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
Methods
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
Results
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Conclusions
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
doi:10.1097/QAI.0b013e3181e674f4
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
17.  Hepatitis B and long-term HIV outcomes in co-infected HAART recipients 
AIDS (London, England)  2009;23(14):1881-1889.
Chronic hepatitis B (CH-B) is common among HIV-infected individuals and increases liver-related mortality in the absence of highly active antiretroviral therapy (HAART). The impact of CH-B on long-term HAART outcomes has not been fully characterized.
Methods
To address this question, HAART initiators enrolled in the Multicenter AIDS Cohort Study (MACS) were retrospectively analyzed. Subjects were classified by hepatitis B category based on serology at the time of HAART initiation. The association of CH-B with mortality, AIDS defining illnesses, CD4 rise, and HIV suppression was assessed using regression analysis.
Results
Of 816 men followed for a median of 7 years on HAART, 350 were never HBV infected, 357 had past infection, 45 had CH-B, and 64 were only core-antibody positive. Despite HAART, AIDS-related mortality was the most common cause of death (8.3/1000 person-years (PYs)). It was highest in those with CH-B (17/1000 PYs, 95% CI 7.3, 42) and lowest among never HBV infected (2.9/1000 PYs, 95% CI 1.4, 6.4). In a multivariable model, patients with CH-B had a 2.7-fold higher incidence of AIDS-related mortality compared to those never infected (P=0.08). Non-AIDS-related mortality was also highest among those with CH-B (22/1000 PYs), primarily due to liver disease (compared to never infected, adjusted HR 4.1, p=0.04). There was no significant difference in AIDS defining events, HIV RNA suppression, and CD4 increase.
Conclusion
In HIV-infected patients receiving long-term HAART, HBV status did not influence HIV suppression or CD4 increase. However, mortality was highest among those with CH-B and was mostly due to liver disease despite HBV-active HAART.
doi:10.1097/QAD.0b013e32832e463a
PMCID: PMC2861825  PMID: 19550291
hepatitis B; HIV; HAART; CD4; mortality; isolated core hepatitis B
18.  Persistent Kaposi sarcoma in the era of HAART: characterizing the predictors of clinical response 
AIDS (London, England)  2008;22(8):937-945.
Objectives
To evaluate the role of highly active antiretroviral therapy (HAART) and chemotherapy on tumor response among persons with AIDS-related Kaposi sarcoma (KS) and identify factors associated with response in a clinic setting.
Design
Retrospective cohort.
Methods
114 patients from two HIV clinics with a diagnosis of KS were identified via a clinical database. Records were reviewed to confirm KS diagnosis and abstract clinical and chemotherapy information. Demographics, laboratory values, and HAART use were abstracted electronically. Cox's proportional hazards models identified predictors of KS improvement and resolution.
Results
Thirty-six months following KS diagnosis, the rate of improvement among 64 patients with confirmed KS was 77%, and the rate of complete resolution 51%. In univariate analyses, recent chemotherapy was associated with KS improvement, and recent HIV viral load and HAART were associated with both improvement and resolution. No measured baseline characteristics (tumor stage, diagnosis year, CD4 T-cell count, HIV viral load, or prior HAART history) or recent CD4 T-cell counts predicted improvement or resolution. In multivariate analyses, recent chemotherapy (HR=5.5, 95% CI: 2.7-11.2, p<0.001) and HAART (HR=4.1, 95% CI: 1.4-12.6, p=0.01) were predictors of improvement; only recent HAART was associated with resolution (HR=6.2, 95% CI: 1.5-26.4, p=0.01). Response was not associated with type of HAART regimen (NNRTI-based, PI-based, or ritonavir-boosted PI-based).
Conclusions
HAART and chemotherapy are important in clinical KS response. Despite widespread availability of HAART and chemotherapy, KS continues to be a clinical problem; only half the patients achieved complete resolution of disease. New therapeutic approaches are needed.
doi:10.1097/QAD.0b013e3282ff6275
PMCID: PMC2730951  PMID: 18453853
Kaposi sarcoma; HAART; chemotherapy; human herpesvirus 8; HIV/AIDS
19.  Influence of Age and Neurotoxic HAART Use on Frequency of HIV Sensory Neuropathy 
AIDS Research and Treatment  2012;2012:961510.
Background. Sensory neuropathy (SN) is one of the most common AIDS-associated neurologic disorders especially in the era of highly active antiretroviral therapy (HAART). The aim of this study was to determine the prevalence of SN among highly-active-antiretroviral-therapy- (HAART-) experienced and HAART-naïve HIV-positive individuals and to investigate the relationship to demographic, clinical, and laboratory factors. Methods. 323 patients with HIV infection (142 on HAART and 181 HAART naïve) were enrolled in a cross-sectional neuropathy screening program. Data was collected using structured questionnaires which contained the brief peripheral neuropathy screening tool of AIDS Clinical Trial Group protocol. Neuropathy was defined by the presence of at least 1 clinical sign in a distal, symmetrical pattern. Patients were classified as symptomatic if they described aching, stabbing, or burning pain, paresthesia, or numbness in a similar distribution. Demographic, clinical, and laboratory details were documented as risk factors. Result. The prevalence of sensory neuropathy was 39.0% (126/323), (of which 29/126 (23%)) were symptomatic. Amongst those on HAART, 60/142 (42.3%) had SN compared to 66/181 (36.5%) HAART-naïve individuals (P = 0.29). On multivariate analyses, the independent associations with SN were increasing age (P = 0.03) and current exposure to stavudine (P = 0.00). Gender (P = 0.99) height (P = 0.07) use of HAART (P = 0.50), duration of HAART treatment (P = 0.10), and lower CD4 count (P = 0.12) were not associated with an increased SN risk. Conclusion. HIV SN remains common despite improved immunologic function associated with HAART and decreased neurotoxic HAART use. In this cross-sectional analysis, age and stavudine-based therapies were the independent risk factors.
doi:10.1155/2012/961510
PMCID: PMC3337556  PMID: 22570772
20.  Preliminary outcomes of a paediatric highly active antiretroviral therapy cohort from KwaZulu-Natal, South Africa 
BMC Pediatrics  2007;7:13.
Background
Few studies address the use of paediatric highly active antiretroviral therapy (HAART) in Africa.
Methods
We performed a retrospective cohort study to investigate preliminary outcomes of all children eligible for HAART at Sinikithemba HIV/AIDS clinic in KwaZulu-Natal, South Africa. Immunologic, virologic, clinical, mortality, primary caregiver, and psychosocial variables were collected and analyzed.
Results
From August 31, 2003 until October 31, 2005, 151 children initiated HAART. The median age at HAART initiation was 5.7 years (range 0.3–15.4). Median follow-up time of the cohort after HAART initiation was 8 months (IQR 3.5–13.5). The median change in CD4% from baseline (p < 0.001) was 10.2 (IQR 5.0–13.8) at 6 months (n = 90), and 16.2 (IQR 9.6–20.3) at 12 months (n = 59). Viral loads (VLs) were available for 100 children at 6 months of which 84% had HIV-1 RNA levels ≤ 50 copies/mL. At 12 months, 80.3% (n = 61) had undetectable VLs. Sixty-five out of 88 children (73.8%) reported a significant increase (p < 0.001) in weight after the first month. Eighty-nine percent of the cohort (n = 132) reported ≤ 2 missed doses during any given treatment month (> 95%adherence). Seventeen patients (11.3%) had a regimen change; two (1.3%) were due to antiretroviral toxicity. The Kaplan-Meier one year survival estimate was 90.9% (95%confidence interval (CI) 84.8–94.6). Thirteen children died during follow-up (8.6%), one changed service provider, and no children were lost to follow-up. All 13 deaths occurred in children with advanced HIV disease within 5 months of treatment initiation. In multivariate analysis of baseline variables against mortality using Cox proportional-hazards model, chronic gastroenteritis was associated with death [hazard ratio (HR), 12.34; 95%CI, 1.27–119.71) and an HIV-positive primary caregiver was found to be protective against mortality [HR, 0.12; 95%CI, 0.02–0.88). Age, orphanhood, baseline CD4%, and hemoglobin were not predicators of mortality in our cohort. Fifty-two percent of the cohort had at least one HIV-positive primary caregiver, and 38.4% had at least one primary caregiver also on HAART at Sinikithemba clinic.
Conclusion
This report suggests that paediatric HAART can be effective despite the challenges of a resource-limited setting.
doi:10.1186/1471-2431-7-13
PMCID: PMC1847430  PMID: 17367540
21.  Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort 
AIDS (London, England)  2009;23(5):631-636.
Background
The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa.
Methods
Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk.
Results
Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed [incidence rate ratio (IRR) = 6.2/100 person-years; 95% CI 5.5–7.0]. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2–8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4–6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4–7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02–7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis [adjusted hazard ratio (aHR) = 0.36; 95% CI 0.25–0.51], and patients receiving HAART after IPT had a 89% reduced hazard (aHR = 0.11; 95% CI 0.02–0.78).
Conclusion
Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.
doi:10.1097/QAD.0b013e328327964f
PMCID: PMC3063949  PMID: 19525621
HAART; isoniazid; preventive treatment; sub-Saharan Africa; tuberculosis
22.  Long-Term Effects of Highly Active Antiretroviral Therapy on CD4+ Cell Evolution among Children and Adolescents Infected with HIV: 5 Years and Counting 
Background
Lower percentages of CD4+ T lymphocytes are associated with adverse clinical outcomes among children and adolescents infected with human immunodeficiency virus (HIV). CD4+ lymphocyte percentage generally increases with receipt of highly active antiretroviral therapy (HAART), but long-term follow-up is required to assess whether these increases in CD4+ cell percentage are maintained and whether they lead to normal CD4+ cell percentages in children with severe immunosuppression.
Methods
The study population included 1236 children and adolescents perinatally infected with HIV who were enrolled in a US-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C) and who were not receiving HAART at study initiation. We estimated the effects of HAART, HAART with protease inhibitors, and HAART with nonnucleoside reverse-transcriptase inhibitors on CD4+ cell percentage, using marginal structural models to account for confounding by severity.
Results
Initiation of any type of HAART increased CD4+ cell percentage by 2.34% (95% confidence interval, 1.35%–3.33%) in the first year, relative to noninitiation of HAART. The substantial increases in CD4+ cell percentage observed after the first year of experience with these combination therapies were followed by relatively smaller increases that continued for 5 years after initiation. Although larger increases in CD4+ cell percentage were observed among children with a greater degree of immunosuppression at baseline, the mean CD4+ cell percentage after 5 years of HAART did not reach normal levels.
Conclusions
Our study supports the initiation of HAART in children before severe immunosuppression occurs for long-term maintenance of normal CD4+ cell percentages. This beneficial result must be weighed against the evidence of potential adverse events associated with the prolonged use of such therapy.
doi:10.1086/587900
PMCID: PMC3154876  PMID: 18426371
23.  Adherence to Highly Active Antiretroviral Treatment in HIV-Infected Rwandan Women 
PLoS ONE  2011;6(11):e27832.
Background
Scale-up of highly active antiretroviral treatment therapy (HAART) programs in Rwanda has been highly successful but data on adherence is limited. We examined HAART adherence in a large cohort of HIV+ Rwandan women.
Methods
The Rwanda Women's Interassociation Study Assessment (RWISA) was a prospective cohort study that assessed effectiveness and toxicity of ART. We analyzed patient data 12±3 months after HAART initiation to determine adherence rates in HIV+ women who had initiated HAART.
Results
Of the 710 HIV+ women at baseline, 490 (87.2%) initiated HAART. Of these, 6 (1.2%) died within 12 months, 15 others (3.0%) discontinued the study and 80 others (19.0%) remained in RWISA but did not have a post-HAART initiation visit that fell within the 12±3 month time points leaving 389 subjects for analysis. Of these 389, 15 women stopped their medications without being advised to do so by their doctors. Of the remaining 374 persons who reported current HAART use 354 completed the adherence assessment. All women, 354/354, reported 100% adherence to HAART at the post-HAART visit. The high self-reported level of adherence is supported by changes in laboratory measures that are influenced by HAART. The median (interquartile range) CD4 cell count measured within 6 months prior to HAART initiation was 185 (128, 253) compared to 264 (182, 380) cells/mm3 at the post-HAART visit. Similarly, the median (interquartile range) MCV within 6 months prior to HAART initiation was 88 (83, 93) fL compared to 104 (98, 110) fL at the 12±3 month visit.
Conclusion
Self-reported adherence to antiretroviral treatment 12±3 months after initiating therapy was 100% in this cohort of HIV-infected Rwandan women. Future studies should explore country-specific factors that may be contributing to high levels of adherence to HAART in this population.
doi:10.1371/journal.pone.0027832
PMCID: PMC3219684  PMID: 22114706
24.  Pregnancy and Virologic Response to Antiretroviral Therapy in South Africa 
PLoS ONE  2011;6(8):e22778.
Background
Although women of reproductive age are the largest group of HIV-infected individuals in sub-Saharan Africa, little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in that setting. We examined the effect of incident pregnancy after HAART initiation on virologic response to HAART.
Methods and Findings
We evaluated a prospective clinical cohort of adult women who initiated HAART in Johannesburg, South Africa between 1 April 2004 and 30 September 2009, and followed up until an event, death, transfer, drop-out, or administrative end of follow-up on 31 March 2010. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study; final sample size for analysis was 5,494 women. Main exposure was incident pregnancy, experienced by 541 women; main outcome was virologic failure, defined as a failure to suppress virus to ≤400 copies/ml by six months or virologic rebound >400 copies/ml thereafter. We calculated adjusted hazard ratios using marginal structural Cox proportional hazards models and weighted lifetable analysis to calculate adjusted five-year risk differences. The weighted hazard ratio for the effect of pregnancy on time to virologic failure was 1.34 (95% confidence limit [CL] 1.02, 1.78). Sensitivity analyses generally confirmed these main results.
Conclusions
Incident pregnancy after HAART initiation was associated with modest increases in both relative and absolute risks of virologic failure, although uncontrolled confounding cannot be ruled out. Nonetheless, these results reinforce that family planning is an essential part of care for HIV-positive women in sub-Saharan Africa. More work is needed to confirm these findings and to explore specific etiologic pathways by which such effects may operate.
doi:10.1371/journal.pone.0022778
PMCID: PMC3149058  PMID: 21829650
25.  Can herpes simplex virus type 2 suppression slow HIV disease progression: a study protocol for the VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial 
Trials  2010;11:113.
Background
Although highly active antiretroviral therapy (HAART) has dramatically decreased HIV-related morbidity and mortality, the associated costs, toxicities, and resistance risks make the potential delay of HAART initiation an attractive goal. Suppression of herpes simplex virus type 2 (HSV-2) may be a novel strategy for achieving this goal because HSV-2 is associated with clinically significant increases in HIV viral load, the primary driver of HIV disease progression.
Methods/Design
The VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial is a multicentre, randomized, fully blinded, clinical trial of twice daily valacyclovir 500 mg versus placebo for delaying the need for initiating HAART among HIV-1, HSV-2 co-infected HAART-naïve adults. 480 participants from Canada, Brazil and Argentina will undergo quarterly clinical follow-up until reaching the composite primary endpoint of having a CD4+ T-cell count ≤ 350 cells/mm3 or initiation of HAART for any reason, whichever occurs first. The primary analysis will use a proportional hazards model, stratified by site, to estimate the relative risk of progression to this endpoint associated with valacyclovir. Secondary analyses will compare the rates of change in CD4 count, median log10 HIV viral load, drug-related adverse events, frequency of HSV reactivations, rate of acyclovir-resistant HSV, and quality of life between study arms.
Discussion
Although HIV treatment guidelines continue to evolve, with some authorities recommending earlier HAART among asymptomatic individuals, the potential delay of HAART remains a clinically relevant goal for many. If shown to be of benefit, implementation of the VALIDATE intervention will require careful consideration of both individual patient-level and public health implications.
Trial Registration
Current Controlled Trials ISRCTN66756285
ClinicalTrials.gov NCT00860977
doi:10.1186/1745-6215-11-113
PMCID: PMC3002348  PMID: 21106086

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