Antiretroviral therapy (ART) adherence among people living with HIV/AIDS (PLHIV) in the north of Vietnam : a multi-method approach

The antiretroviral therapy (ART) program for People Living with HIV/AIDS (PLHIV) in Vietnam has been scaled up rapidly in recent years (from 50 clients in 2003 to almost 38,000 in 2009). ART success is highly dependent on the ability of the patients to fully adhere to the prescribed treatment regimen. Despite the remarkable extension of ART programs in Vietnam, HIV/AIDS program managers still have little reliable data on levels of ART adherence and factors that might promote or reduce adherence. Several previous studies in Vietnam estimated extremely high levels of ART adherence among their samples, although there are reasons to question the veracity of the conclusion that adherence is nearly perfect. Further, no study has quantitatively assessed the factors influencing ART adherence. In order to reduce these gaps, this study was designed to include several phases and used a multi-method approach to examine levels of ART non-adherence and its relationship to a range of demographic, clinical, social and psychological factors. The study began with an exploratory qualitative phase employing four focus group discussions and 30 in-depth interviews with PLHIV, peer educators, carers and health care providers (HCPs). Survey interviews were completed with 615 PLHIV in five rural and urban out-patient clinics in northern Vietnam using an Audio Computer Assisted Self-Interview (ACASI) and clinical records extraction. The survey instrument was carefully developed through a systematic procedure to ensure its reliability and validity. Cultural appropriateness was considered in the design and implementation of both the qualitative study and the cross sectional survey. The qualitative study uncovered several contrary perceptions between health care providers and HIV/AIDS patients regarding the true levels of ART adherence. Health care providers often stated that most of their patients closely adhered to their regimens, while PLHIV and their peers reported that “it is not easy” to do so. The quantitative survey findings supported the PLHIV and their peers’ point of view in the qualitative study, because non-adherence to ART was relatively common among the study sample. Using the ACASI technique, the estimated prevalence of onemonth non-adherence measured by the Visual Analogue Scale (VAS) was 24.9% and the prevalence of four-day not-on-time-adherence using the modified Adult AIDS Clinical Trials Group (AACTG) instrument was 29%. Observed agreement between the two measures was 84% and kappa coefficient was 0.60 (SE=0.04 and p<0.0001). The good agreement between the two measures in the current study is consistent with those found in previous research and provides evidence of cross-validation of the estimated adherence levels. The qualitative study was also valuable in suggesting important variables for the survey conceptual framework and instrument development. The survey confirmed significant correlations between two measures of ART adherence (i.e. dose adherence and time adherence) and many factors identified in the qualitative study, but failed to find evidence of significant correlations of some other factors and ART adherence. Non-adherence to ART was significantly associated with untreated depression, heavy alcohol use, illicit drug use, experiences with medication side-effects, chance health locus of control, low quality of information from HCPs, low satisfaction with received support and poor social connectedness. No multivariate association was observed between ART adherence and age, gender, education, duration of ART, the use of adherence aids, disclosure of ART, patients’ ability to initiate communication with HCPs or distance between clinic and patients’ residence. This is the largest study yet reported in Asia to examine non-adherence to ART and its possible determinants. The evidence strongly supports recent calls from other developing nations for HIV/AIDS services to provide screening, counseling and treatment for patients with depressive symptoms, heavy use of alcohol and substance use. Counseling should also address fatalistic beliefs about chance or luck determining health outcomes. The data suggest that adherence could be enhanced by regularly providing information on ART and assisting patients to maintain social connectedness with their family and the community. This study highlights the benefits of using a multi-method approach in examining complex barriers and facilitators of medication adherence. It also demonstrated the utility of the ACASI interview method to enhance open disclosure by people living with HIV/AIDS and thus, increase the veracity of self-reported data.

Human papillomavirus prevalence, viral load and pre-cancerous lesions of the cervix in women initiating highly active antiretroviral therapy in South Africa : a cross-sectional study

Background Cervical cancer and infection with human immunodeficiency virus (HIV) are both important public health problems in South Africa (SA). The aim of this study was to determine the prevalence of cervical squamous intraepithelial lesions (SILs), high-risk human papillomavirus (HR-HPV), HPV viral load and HPV genotypes in HIV positive women initiating anti-retroviral (ARV) therapy. Methods A cross-sectional survey was conducted at an anti-retroviral (ARV) treatment clinic in Cape Town, SA in 2007. Cervical specimens were taken for cytological analysis and HPV testing. The Digene Hybrid Capture 2 (HC2) test was used to detect HR-HPV. Relative light units (RLU) were used as a measure of HPV viral load. HPV types were determined using the Roche Linear Array HPV Genotyping test. Crude associations with abnormal cytology were tested and multiple logistic regression was used to determine independent risk factors for abnormal cytology. Results The median age of the 109 participants was 31 years, the median CD4 count was 125/mm3, 66.3% had an abnormal Pap smear, the HR-HPV prevalence was 78.9% (Digene), the median HPV viral load was 181.1 RLU (HC2 positive samples only) and 78.4% had multiple genotypes. Among women with abnormal smears the most prevalent HR-HPV types were HPV types 16, 58 and 51, all with a prevalence of 28.5%. On univariate analysis HR-HPV, multiple HPV types and HPV viral load were significantly associated with the presence of low and high-grade SILs (LSIL/HSIL). The multivariate logistic regression showed that HPV viral load was associated with an increased odds of LSIL/HSIL, odds ratio of 10.7 (95% CI 2.0 – 57.7) for those that were HC2 positive and had a viral load of ≤ 181.1 RLU (the median HPV viral load), and 33.8 (95% CI 6.4 – 178.9) for those that were HC2 positive with a HPV viral load > 181.1 RLU. Conclusion Women initiating ARVs have a high prevalence of abnormal Pap smears and HR-HPV. Our results underscore the need for locally relevant, rigorous screening protocols for the increasing numbers of women accessing ARV therapy so that the benefits of ARVs are not partially offset by an excess risk in cervical cancer.

Factors associated with suboptimal adherence to antiretroviral therapy in Viet Nam: A cross-sectional study using audio computer-assisted self-interview (ACASI)

Background: Optimal adherence to antiretroviral therapy (ART) is necessary for people living with HIV/AIDS (PLHIV). There have been relatively few systematic analyses of factors that promote or inhibit adherence to antiretroviral therapy among PLHIV in Asia. This study assessed ART adherence and examined factors associated with suboptimal adherence in northern Viet Nam. Methods: Data from 615 PLHIV on ART in two urban and three rural outpatient clinics were collected by medical record extraction and from patient interviews using audio computer-assisted self-interview (ACASI). Results: The prevalence of suboptimal adherence was estimated to be 24.9% via a visual analogue scale (VAS) of past-month dose-missing and 29.1% using a modified Adult AIDS Clinical Trial Group scale for on-time dose-taking in the past 4 days. Factors significantly associated with the more conservative VAS score were: depression (p < 0.001), side-effect experiences (p < 0.001), heavy alcohol use (p = 0.001), chance health locus of control (p = 0.003), low perceived quality of information from care providers (p = 0.04) and low social connectedness (p = 0.03). Illicit drug use alone was not significantly associated with suboptimal adherence, but interacted with heavy alcohol use to reduce adherence (p < 0.001). Conclusions: This is the largest survey of ART adherence yet reported from Asia and the first in a developing country to use the ACASI method in this context. The evidence strongly indicates that ART services in Viet Nam should include screening and treatment for depression, linkage with alcohol and/or drug dependence treatment, and counselling to address the belief that chance or luck determines health outcomes.

An economic case for providing free access to antiretroviral therapy for HIV-positive people in South Australia

Background As financial constraints can be a barrier to accessing HIV antiretroviral therapy (ART), we argue for the removal of copayment requirements from HIV medications in South Australia. Methods Using a simple mathematical model informed by available behavioural and biological data and reflecting the HIV epidemiology in South Australia, we calculated the expected number of new HIV transmissions caused by persons who are not currently on ART compared with transmissions for people on ART. The extra financial investment required to cover the copayments to prevent an HIV infection was compared with the treatment costs saved due to averting HIV infections. Results It was estimated that one HIV infection is prevented per year for every 31.4 persons (median, 24.0–42.7 interquartile range (IQR)) who receive treatment. By considering the incremental change in costs and outcomes of a change in program from the current status quo, it would cost the health sector $17 860 per infection averted (median, $13 651–24 287 IQR) if ART is provided as a three-dose, three-drug combination without requirements for user-pay copayments. Conclusions The costs of removing copayment fees for ART are less than the costs of treating extra HIV infections that would result under current conditions. Removing the copayment requirement for HIV medication would be cost-effective from a governmental perspective.

Combination antiretroviral therapy -associated lipodystrophy : insights into pathogenesis and treatment

Introduction: Combination antiretroviral therapy (cART) has decreased morbidity and mortality of individuals infected with human immunodeficiency virus type 1 (HIV-1). Its use, however, is associated with adverse effects which increase the patients risk of conditions such as diabetes and coronary heart disease. Perhaps the most stigmatizing side effect is lipodystrophy, i.e., the loss of subcutaneous adipose tissue (SAT) in the face, limbs and trunk while fat accumulates intra-abdominally and dorsocervically. The pathogenesis of cART-associated lipodystrophy is obscure. Nucleoside reverse transcriptase inhibitors (NRTI) have been implicated to cause lipoatrophy via mitochondrial toxicity. There is no known effective treatment for cART-associated lipodystrophy during unchanged antiretroviral regimen in humans, but in vitro data have shown uridine to abrogate NRTI-induced toxicity in adipocytes. Aims: To investigate whether i) cART or lipodystrophy associated with its use affect arterial stiffness; ii) lipoatrophic SAT is inflamed compared to non-lipoatrophic SAT; iii) abdominal SAT from patients with compared to those without cART-associated lipoatrophy differs with respect to mitochondrial DNA (mtDNA) content, adipose tissue inflammation and gene expression, and if NRTIs stavudine and zidovudine are associated with different degree of changes; iv) lipoatrophic abdominal SAT differs from preserved dorsocervical SAT with respect to mtDNA content, adipose tissue inflammation and gene expression in patients with cART-associated lipodystrophy and v) whether uridine can revert lipoatrophy and the associated metabolic disturbances in patients on stavudine or zidovudine based cART. Subjects and methods: 64 cART-treated patients with (n=45) and without lipodystrophy/-atrophy (n=19) were compared cross-sectionally. A marker of arterial stiffness, heart rate corrected augmentation index (AgIHR), was measured by pulse wave analysis. Body composition was measured by magnetic resonance imaging and dual-energy X-ray absorptiometry, and liver fat content by proton magnetic resonance spectroscopy. Gene expression and mtDNA content in SAT were assessed by real-time polymerase chain reaction and microarray. Adipose tissue composition and inflammation were assessed by histology and immunohistochemistry. Dorsocervical and abdominal SAT were studied. The efficacy and safety of uridine for the treatment of cART-associated lipoatrophy were evaluated in a randomized, double-blind, placebo-controlled 3-month trial in 20 lipoatrophic cART-treated patients. Results: Duration of antiretroviral treatment and cumulative exposure to NRTIs and protease inhibitors, but not the presence of cART-associated lipodystrophy, predicted AgIHR independent of age and blood pressure. Gene expression of inflammatory markers was increased in SAT of lipodystrophic as compared to non-lipodystrophic patients. Expression of genes involved in adipogenesis, triglyceride synthesis and glucose disposal was lower and of those involved in mitochondrial biogenesis, apoptosis and oxidative stress higher in SAT of patients with than without cART-associated lipoatrophy. Most changes were more pronounced in stavudine-treated than in zidovudine-treated individuals. Lipoatrophic SAT had lower mtDNA than SAT of non-lipoatrophic patients. Expression of inflammatory genes was lower in dorsocervical than in abdominal SAT. Neither depot had characteristics of brown adipose tissue. Despite being spared from lipoatrophy, dorsocervical SAT of lipodystrophic patients had lower mtDNA than the phenotypically similar corresponding depot of non-lipodystrophic patients. The greatest difference in gene expression between dorsocervical and abdominal SAT, irrespective of lipodystrophy status, was in expression of homeobox genes that regulate transcription and regionalization of organs during embryonal development. Uridine increased limb fat and its proportion of total fat, but had no effect on liver fat content and markers of insulin resistance. Conclusions: Long-term cART is associated with increased arterial stiffness and, thus, with higher cardiovascular risk. Lipoatrophic abdominal SAT is characterized by inflammation, apoptosis and mtDNA depletion. As mtDNA is depleted even in non-lipoatrophic dorsocervical SAT, lipoatrophy is unlikely to be caused directly by mtDNA depletion. Preserved dorsocervical SAT of patients with cART-associated lipodystrophy is less inflamed than their lipoatrophic abdominal SAT, and does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal SAT is in expression of transcriptional regulators, homeobox genes, which might explain the differential susceptibility of these adipose tissue depots to cART-induced toxicity. Uridine is able to increase peripheral SAT in lipoatrophic patients during unchanged cART.

Patient Retention in Antiretroviral Therapy Programs in Sub-Saharan Africa: A Systematic Review

Paper published in PLoS Medicine in 2007.

Rationing Antiretroviral Therapy for HIV/AIDS in Africa: Efficiency, Equity, and Reality

Background: Rationing of access to antiretroviral therapy already exists in sub-Saharan Africa and will intensify as national treatment programs develop. The number of people who are medically eligible for therapy will far exceed the human, infrastructural, and financial resources available, making rationing of public treatment services inevitable. Methods: We identified 15 criteria by which antiretroviral therapy could be rationed in African countries and analyzed the resulting rationing systems across 5 domains: clinical effectiveness, implementation feasibility, cost, economic efficiency, and social equity. Findings: Rationing can be explicit or implicit. Access to treatment can be explicitly targeted to priority subpopulations such as mothers of newborns, skilled workers, students, or poor people. Explicit conditions can also be set that cause differential access, such as residence in a designated geographic area, co-payment, access to testing, or a demonstrated commitment to adhere to therapy. Implicit rationing on the basis of first-come, first-served or queuing will arise when no explicit system is enforced; implicit systems almost always allow a high degree of queue-jumping by the elite. There is a direct tradeoff between economic efficiency and social equity. Interpretation: Rationing is inevitable in most countries for some period of time. Without deliberate social policy decisions, implicit rationing systems that are neither efficient nor equitable will prevail. Governments that make deliberate choices, and then explain and defend those choices to their constituencies, are more likely to achieve a socially desirable outcome from the large investments now being made than are those that allow queuing and queue-jumping to dominate.

How Much Does It Cost to Provide Antiretroviral Therapy for HIV/AIDS in Africa?

Background: Many African countries are rapidly expanding HIV/AIDS treatment programs. Empirical information on the cost of delivering antiretroviral therapy (ART) for HIV/AIDS is needed for program planning and budgeting. Methods: We searched published and gray sources for estimates of the cost of providing ART in service delivery (non-research) settings in sub-Saharan Africa. Estimates were included if they were based on primary local data for input prices. Results: 17 eligible cost estimates were found. Of these, 10 were from South Africa. The cost per patient per year ranged from $396 to $2,761. It averaged approximately $850/patient/year in countries outside South Africa and $1,700/patient/year in South Africa. The most recent estimates for South Africa averaged $1,200/patient/year. Specific cost items included in the average cost per patient per year varied, making comparison across studies problematic. All estimates included the cost of antiretroviral drugs and laboratory tests, but many excluded the cost of inpatient care, treatment of opportunistic infections, and/or clinic infrastructure. Antiretroviral drugs comprised an average of one third of the cost of treatment in South Africa and one half to three quarters of the cost in other countries. Conclusions: There is very little empirical information available about the cost of providing antiretroviral therapy in non-research settings in Africa. Methods for estimating costs are inconsistent, and many estimates combine data drawn from disparate sources. Cost analysis should become a routine part of operational research on the treatment rollout in Africa.

Non-clinical outcomes of antiretroviral therapy for HIV/AIDS in developing countries: a systematic literature review

The impacts of antiretroviral therapy on quality of life, mental health, labor productivity, and economic wellbeing for people living with HIV/AIDS in developing countries are only beginning to be measured. We conducted a systematic literature review to analyze the effect of antiretroviral therapy (ART) on these non-clinical indicators in developing countries and assess the state of research on these topics. Both qualitative and quantitative studies were included, as were peer-reviewed articles, gray literature, and conference abstracts and presentations. Findings are reported from 12 full-length articles, 7 abstracts, and 1 presentation (representing 16 studies). Compared to HIV-positive patients not yet on treatment, patients on ART reported significant improvements in physical, emotional and mental health and daily function. Work performance improved and absenteeism decreased, with the most dramatic changes occurring in the first three months of treatment and then leveling off. Little research has been done on the impact of ART on household wellbeing, with modest changes in child and family wellbeing within households where adults are receiving ART reported so far. Studies from developing countries have not yet assessed non-clinical outcomes of therapy beyond the first year; therefore, longitudinal outcomes are still unknown. As ART roll out extends throughout high HIV prevalence, low-resource countries and is sustained over years and decades, both positive and adverse non-clinical outcomes need to be empirically measured and qualitatively explored in order to support patient adherence and maximize treatment benefits.

Effectiveness of rescue antiretroviral therapy including intravenously administered zidovudine and foscarnet in a child with HIV-1 enteropathy.

Case Reports

Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy.

BACKGROUND: Conflicting results have been reported among studies of protease inhibitor (PI) use during pregnancy and preterm birth. Uncontrolled confounding by indication may explain some of the differences among studies. METHODS: In total, 777 human immunodeficiency virus (HIV)-infected pregnant women in a prospective cohort who were not receiving antiretroviral (ARV) treatment at conception were studied. Births <37 weeks gestation were reviewed, and deliveries due to spontaneous labor and/or rupture of membranes were identified. Risk of preterm birth and low birth weight (<2500 g) were evaluated by using multivariable logistic regression. RESULTS: Of the study population, 558 (72%) received combination ARV with PI during pregnancy, and a total of 130 preterm births were observed. In adjusted analyses, combination ARV with PI was not significantly associated with spontaneous preterm birth, compared to ARV without PI (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.70-2.12). Sensitivity analyses that included women who received ARV prior to pregnancy also did not identify a significant association (OR, 1.34; 95% CI, 0.84-2.16). Low birth weight results were similar. CONCLUSIONS: No evidence of an association between use of combination ARV with PI during pregnancy and preterm birth was found. Our study supports current guidelines that promote consideration of combination ARV for all HIV-infected pregnant women.

Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial.

BACKGROUND: To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. METHODS: Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. RESULTS: Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]). CONCLUSION: Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.

Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up.

BACKGROUND: In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up. METHODS: This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained. RESULTS: 161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01). CONCLUSIONS: After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.

CD4 enumeration technologies: a systematic review of test performance for determining eligibility for antiretroviral therapy.

BACKGROUND: Measurement of CD4+ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration. METHODS AND FINDINGS: Studies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/μl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/μl, bias ranged from -35.2 to +13.1 cells/μl while at counts >350 cells/μl, bias ranged from -70.7 to +47 cells/μl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/μl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained. CONCLUSIONS: A wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed.