Annual Costs Incurred in Managing Adverse Drug Reactions Attributable to Fixed-Dose Combination Highly Active Antiretroviral Therapy in an Outpatient Antiretroviral Clinic in Gauteng: A Budget Impact Analysis.

OBJECTIVES: This study aimed to identify adverse drug reactions (ADRs) attributable to tenofovir (TDF)- and zidovudine (AZT)-based fixed-dose combinations of highly active antiretroviral (ARV) therapy and subsequently determine the annual costs incurred in managing these ADRs and the budget implications in an outpatient ARV clinic in Mamelodi, Pretoria. METHODS: This retrospective cohort study reviewed deidentified clinical data for ADRs. Medical charts of human immunodeficiency virus-positive patients, who were receiving either TDF- or AZT-based fixed-dose combinations of ARV therapy, were analyzed. Costs were converted to US dollars using the rate of US$1 equivalent to ZAR14.3853. Based on the costs and the incidence rates of ADRs observed in the analysis, a decision tree model was established to estimate the cost impact of ADR management on the clinic's budget. RESULTS: A total of 469 patient files were analyzed (62% female vs 38% male). The mean age at the start of ARV therapy for the cohort was 36.6 years (95% confidence interval 35.74-37.45), and the mean baseline CD4 count was 380 (95% confidence interval 343-418). The incidence of ADRs to TDF- or AZT-based fixed-dose combinations of ARV therapy was found to be 24.95%. The study revealed that US$29.70 was the cost attributed to ADRs owing to TDF-based regimens, whereas US$32.53 was the cost attributed to ADRs owing to AZT-based regimens, per patient, annually. Costs attributed to gastrointestinal-related ADRs were the highest in comparison with other ADRs. The estimated total cost of ADRs attributed to AZT-based therapy was US$556.40, and the estimated total cost of ADRs attributed to TDF-based ARV therapy per annum was US$2348.80 for the 1221 patients who started receiving ARV therapy between July 2017 and June 2018 at the clinic. CONCLUSIONS: Despite the estimated costs related to ADRs in the study being lower than those in similar studies, there remains a notable budget impact, particularly in a resource-limited setting. The study findings allow for improved budget forecasts in an ARV clinic setting.

Vitamin D Assessment Over 48 Weeks in Treatment-Naive HIV Individuals Starting Lopinavir/Ritonavir Monotherapy.

BACKGROUND: Vitamin D deficiency is common in HIV population and has been associated with increased comorbidity risk and poor immunologic status. OBJECTIVE: To evaluate the effect of protease inhibitor lopinavir/ritonavir monotherapy on changes in serum 25-hydroxyvitamin D [25(OH)D] over 48 weeks. METHODS: Thirty-four treatment-naïve HIV individuals initiating lopinavir/ritonavir monotherapy and receiving clinical care from private practice in Houston, Texas, were included. Serum 25-hydroxyvitamin D levels from stored plasma samples collected from IMANI-2 pilot study at both baseline and 48 weeks were analyzed using LC-MS assays. Mean 25(OH)D at baseline and 48 weeks were compared using paired t-tests. Linear regression analysis was used to evaluate factors associated with changes in 25(OH)D. Logistic regression analyses were used to determine the effect of vitamin D status and covariates on CD4 cell count recovery. RESULTS: Mean 25(OH)D was significantly higher at 48 weeks (26.3 ng/mL (SD + 14.9); p=0.0003) compared to baseline (19.8 ng/mL (SD +12.1), with fewer individuals having vitamin D deficiency (41.2%) and severe deficiency (11.8%). Both body mass index and baseline CD4 cell count were significant independent covariates associated with 25(OH)D changes over 48 weeks. Baseline vitamin D status did not affect CD4 cell count recovery. However, in a 24-week multivariate analysis, current tobacco use was significantly associated with a decreased odds of CD4 cell count recovery (AOR 0.106, 95% CI 0.018-0.606; p=0.012). CONCLUSION: Individuals treated with lopinavir/ritonavir monotherapy had significantly higher 25(OH)D after 48 weeks. Current tobacco users had significantly diminished CD4 cell count recovery after starting treatment, warranting further clinical investigation.

Magnitude of Anemia and Associated Factors Among Human Immunodeficiency Virus Infected Children on Highly Active Antiretroviral Therapy at University of Gondar Comprehensive and Specialized Referral Hospital Northwest Ethiopia.

BACKGROUND: Anemia is one of the most common hematological problems in HIV infected patients in the world. The main aim of this study was to determine the magnitude of anemia and associated factors among HIV infected children on highly active antiretroviral therapy attending University of Gondar Comprehensive and Specialized Referral Hospital. METHODS: A retrospective study was conducted from 2013 to 2018 by reviewing medical records at University of Gondar Comprehensive and Specialized Referral Hospital ART clinic. Records of 238 HIV infected children on HAART were selected using a convenient sampling technique. Socio-demographic characteristics, clinical information, and hematological and immunological profiles of the study participants were collected from the patients record books. WHO cutoff value of hemoglobin was taken and adjusted to define anemia in higher altitude. Data was analyzed by using the SPSS version 20 statistical software, and odds ratios with 95% confidence intervals were used to quantify the strength of association between anemia and its potential predictors. RESULTS: The overall prevalence of anemia among HIV infected children in this study was 38.7%. Of anemic children, 48.9% had mild, 39.1% moderate, and 11.9% severe anemia. This study showed that HIV infected children on Highly Active Antiretroviral Therapy who live in rural residence had a two-fold risk of being anemia than urban dwellers (AOR = 2.151, 95% CI, 1.123 - 4.122). There was no significant association with gender, WHO clinical stage, opportunistic infections, cotrimoxazole treatment, and CD4 count percentage. CONCLUSIONS: Anemia is a common problem among the children taking highly active antiretroviral therapy. Therefore, health care workers need to routinely investigate and treat anemia, especially in rural dwellers. Furthermore, large scale and longitudinal studies are recommended to strengthen and explore the problem in depth.

Adverse events in Chinese human immunodeficiency virus (HIV) patients receiving first line antiretroviral therapy.

BACKGROUND: Although the global human immunodeficiency virus (HIV) epidemic has improved significantly due to antiretroviral treatment (ART), ART-related adverse events (AEs) remain an issue. Therefore, investigating the factors associated with ART-related AEs may provide vital information for monitoring risks. METHODS: A prospective cohort study was conducted among adult patients (aged 18 years or older) with HIV who received Tenofovir (TDF) + Lamivudine (3TC) + Efavirenz (EFV) as first-line ART regimens. All AEs during the first 12 months of therapy were recorded. Logistic regression analysis was used to identify variables associated with AEs. RESULTS: Four hundred seventy-four patients receiving TDF+ 3TC+ EFV ART regimens between March 2017 and October 2017 were included in the study analysis. Among them, 472 (99.6%) experienced at least one AE, 436 (92.0%) patients experienced at least one AE within 1 month of treatment, 33 (7.0%) between one and 3 months of treatment, and three (0.6%) patients after 3 months of treatment. The most commonly reported AE was nervous system (95.6%) related, followed by dyslipidemia (79.3%), and impaired liver function (48.1%). Patients with baseline body mass index (BMI) greater than 24 kg/m2 (adjusted OR 1.77, 95%CI 1.03-3.02), pre-existing multiple AEs (adjusted OR 2.72, 95%CI 1.59-4.64), and pre-existing severe AEs (adjusted OR 5.58, 95%CI 2.65-11.73) were at increased odds of developing a severe AE. Patients with baseline BMI greater than 24 kg/m2 (adjusted OR 2.72, 95%CI 1.25-5.89) were more likely to develop multiple AEs. CONCLUSION: The incidence of ART-related adverse events over a 12-month period in China was high. Baseline BMI greater than 24 kg/m2, pre-existing multiple AEs, and pre-existing severe AEs were shown to be independent risk factors for developing a severe AE.

Assessment of liver and renal functions in human immunodeficiency virus-infected persons on highly active antiretroviral therapy: A mixed cohort study.

BACKGROUND: Indian data on potential hepatorenal toxic effects of highly active antiretroviral therapy (HAART) in HIV/AIDS-affected persons is lacking. OBJECTIVES: To assess hepatorenal abnormalities in HIV-infected persons on HAART in a hospital-based mixed cohort study using concurrent and nonconcurrent data analysis. METHODS: Hepatorenal function tests, urinalysis and ultrasonogaphy for liver/kidneys (when applicable) were assessed in 400 (men 185; women 215) persons aged 2-84 (mean 47.8) years on HAART. Acute liver toxicity, acute kidney injury and chronic kidney disease were defined depending upon abnormal serum alanine aminotransferase, urea and creatinine levels/clearance as per standard guidelines. RESULTS: The duration of HAART was 1 month to 9 years (mean 3.7 years) with 284 (71%) individuals being on treatment for ≤5years. The major HAART regimens included zidovudine + lamivudine + nevirapine in 175 (43.8%), tenofovir + lamivudine + efavirenz in 174 (43.5%) and zidovudine + lamivudine + efavirenz in 20 (5%) individuals and were associated with grade-1 hepatic dysfunction in 57 (14.3%) individuals, with men aged between 31 and 45 years on antiretroviral therapy for >5 years being mainly affected. Forty two (17.1%) of 246 individuals with anemia and 15 (9.7%) of 154 individuals without anemia showed hepatic dysfunction. None had acute kidney injury, chronic kidney disease or abnormal urinalysis or ultrasonography. In contrast, the pretreatment elevated serum alanine amiotranerase in 99 (22.3%) and blood urea and/or creatinine levels in 16 (4%) individuals decreased significantly post highly active antiretroviral therapy. CONCLUSIONS: The study reflects the low frequency of regimen based highly active antiretroviral therapy-associated hepatic or nephrotoxicity despite prolonged use, especially in the absence of other risk factors. Preexisting anemia appears an important risk factor for highly active antiretroviral therapy-induced hepatotoxicity (OR 1.90, Cl 95% CI 1.02-3.57, P = 0.04). Highly active antiretroviral therapy-associated nephrotoxicity was not a significant problem. Study of viral load or other risk factors and potential of each drug for hepatorenal toxicity/dysfunction in HIV affected were not part of the study. A small number of subjects and retrospective analysis of biochemical parameters were other important limitations.

Assessment of complex genomic alterations induced by AZT, 3TC, and the combination AZT +3TC.

Highly active antiretroviral therapy (HAART) regimens are based on the use of nucleoside reverse transcriptase inhibitors (NRTIs), which are the main drugs used by patients infected with the human immunodeficiency virus (HIV). The use of NRTIs combinations has afforded clear clinical benefits to patients undergoing HAART. However, the combination of two NRTIs may increase the risk of genomic instability in comparison with the drugs administered individually. We analyzed the ability of zidovudine (AZT) and lamivudine (3TC), and the combination AZT +3TC to induce complex genomic alterations using the cytokinesis-block micronucleus (CBMN) assay in Chinese hamster ovary (CHO)-K1 cells. The 24-h cell treatment with individual NRTIs showed that AZT increased micronucleus frequencies and nucleoplasmic bridges (NPBs). No significant differences were observed for any parameters investigated after exposure of CHO-K1 cells to 3TC. The combination AZT +3TC significantly increased micronucleus frequencies. Analysis of interaction between these drugs suggested that antagonism occurs in all AZT +3TC concentrations. These results highlight the importance to investigate the genotoxic profile of NRTIs to develop safer intervention strategies in antiretroviral treatment protocols.

Liver Fibrosis Assessment in a Cohort of Greek HIV Mono-Infected Patients by Non-Invasive Biomarkers.

BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD) is common in HIV-infected individuals. Liver biopsy remains the gold-standard procedure for the diagnosis of liver fibrosis, but both Transient Elastography (TE) and Non-invasive Biomarkers (NIBMs) have emerged as alternatives. OBJECTIVES: Our study's aim was to validate commonly used NIBMs for the assessment of liver fibrosis in a cohort of Greek HIV-mono-infected patients. METHODS: Inclusion criteria were confirmed HIV-infection and age>18 years and exclusion criteria HBV or HCV seropositivity, liver disease other than NAFLD, alcohol abuse, ascites, transaminases levels>4xULN(upper limit of normal) and Body-Mass index(BMI)>40. Liver stiffness (LS) measurement with TE and thorough laboratory work up and medical history were acquired at study entry. FIB-4, APRI, NFS, BARD, Forns and Lok scores were calculated for each patient. RESULTS: A total of 157 patients were eligible for this study. Significant liver fibrosis, compatible with Metavir score of F3-F4, was found in only 11(7%) patients. These findings were in accordance with those of the NIBMs; the BARD score constituting the only exception, allocating 102(65%) patients as having significant liver fibrosis. In order to obtain a balance between sensitivity and specificity new cut-offs for each NIBM were calculated; FIB-4 score yielded the best results, since by changing the cut-off to 1.49 a sensitivity and specificity balanced for both close to 85% was achieved. CONCLUSION: Our findings suggest that NIBMs can be used for the evaluation of liver fibrosis in HIV mono-infected patients. New cut-offs for NIBMs should probably be calculated, to help distinguishing patients with significant from those with mild/no fibrosis.

Prevalence and related drug cost of comorbidities in HIV-infected patients receiving highly active antiretroviral therapy in Taiwan: A cross-sectional study.

BACKGROUND: To determine the prevalence of chronic comorbidities and associated medication costs in Taiwanese HIV patients in order to increase awareness of the disease burden among healthcare providers and patients. METHODS: HIV-diagnosed patients receiving highly active antiretroviral therapy (HAART; 2010-2013) were identified from the Taiwan National Health Insurance Research Database with the corresponding International Classification of Diseases, ninth revision (ICD-9) code. Comorbidities (type II diabetes mellitus, hypertension, dyslipidemia, major depressive disorder, acute coronary syndrome, and cholelithiasis/nephrolithiasis) were identified according to ICD-9 or relevant medication use. Comorbidity medication and associated costs were identified using the drug classification code from the Anatomical Therapeutic Chemical classification system code series and series outpatient prescriptions. RESULTS: Of 20,726 HIV-diagnosed Taiwanese patients (2010-2013), 13,142 receiving HAART were analyzed. Prevalence of all chronic comorbidities was significantly greater (p < 0.0001) in patients aged ≥40 years versus <40 years (diabetes mellitus, 14.95% vs. 3.30%; hypertension, 46.73% vs. 26.83%; dyslipidemia, 34.93% vs. 18.37%; depression, 23.75% vs. 19.88%; acute coronary syndrome, 1.16% vs. 0.21%; nephrolithiasis/cholelithiasis, 7.26% vs. 4.56%; >2 comorbidities, 24.80% vs. 7.21%). An increase in comorbidity medication spending (2010 vs. 2013 medication costs) was observed (antidyslipidemia, $88,878 vs. $168,180; antihyperglycemia, $32,372 vs. $73,518; antidepressants, $78,220 vs. $125,971; sedatives, $60,009 vs. $85,055; antihypertension, $47,115 vs. $95,134), contributing to overall treatment costs increasing almost two-fold from 2010 to 2013. CONCLUSIONS: Among HIV-infected Taiwanese patients receiving HAART, significant increases in comorbidity prevalence with age, along with rising comorbidity medication costs, suggest the need for preventative as well as chronic care.

Alternative switching strategies based on regimens with a low genetic barrier: do clinicians have a choice nowadays?

Clinicians sometimes use switching strategies based on regimens such as RAL + ABC/3TC or RPV + ABC/3TC in order to resolve tolerability or safety issues associated with conventional recommended first-line strategies. Despite the low genetic barrier of these regimens, high safety and efficacy rates have been reported in retrospective studies.

The transition to dolutegravir and other new antiretrovirals in low-income and middle-income countries: what are the issues?

: There are currently approximately 16 million people taking NNRTI-based first-line treatment in low-income and middle-income countries. Most of these patients are using the combination of tenofovir (TDF), lamivudine (3TC) and efavirenz (EFV). The integrase inhibitor dolutegravir (DTG) has shown an improved safety profile compared with EFV in randomized studies. DTG also has a high barrier to development of drug resistance. New co-formulated tablets with TDF/3TC/DTG are being introduced into LMICs, for a median price of $75 per person-year. The prodrug of TDF, tenofovir alafenamide (TAF) is cheaper to manufacture than TDF. A combined pill with TAF/3TC/DTG is also being launched in LMICs, at a similar low price. However, the clinical development programmes for DTG and TAF did not include extensive analysis of several key populations: pregnant women, people with HIV-tuberculosis (TB) coinfection taking rifampicin-based treatment, and treatment-naive or pretreated patients with NRTI drug resistance. An observational study in Botswana has shown an increased risk of neural tube defects when dolutegravir is used in early pregnancy. In LMICs, only 50% of patients have access to regular viral load testing, and genotypic resistance testing is rarely performed. There is currently no clinical data to support switching patients from TDF/3TC/EFV directly to TDF/3TC/DTG if their viral load is either detectable or unknown. New clinical trials and observational studies will be needed to better understand the consequences of this switch of treatment in LMICs. Clinical trials of new antiretrovirals in key populations should be conducted earlier in their development. This will ensure that new treatments can be introduced into LMICs soon after their launch in high-income countries.

Short-term cost and efficiency analysis of raltegravir versus atazanavir/ritonavir or darunavir/ritonavir for treatment-naive adults with HIV-1 infection in Spain.

INTRODUCTION: The AIDS Clinical Trial Group (ACTG) 5257 clinical trial showed that raltegravir (RAL) was superior to atazanavir/ritonavir (ATV/r) and darunavir/ritonavir (DRV/r), when used in combination with emtricitabine/tenofovir DF (FTC/TDF), in a 96-week composite endpoint combining virologic efficacy and tolerability for treatment-naive adults with HIV-1 infection. This study aimed to estimate the efficiency associated with these three regimens in Spain. METHODS: An economic model was developed to estimate costs for antiretroviral drugs, adverse event management, and HIV care for individuals initiating first-line therapy. Antiretroviral drug costs were based on hospital costs with mandatory discounts applied. Adverse event management costs and HIV care costs were obtained from published sources and inflated to 2015 euros. Head-to-head efficacy and safety data (discontinuation rates, mean CD4 cell-count changes, adverse event incidence) up to 96 weeks for each regimen were obtained from the clinical trial. The efficiency of each regimen, as measured by the cost per successfully treated patient (i.e. on first-line therapy for 96 weeks), was estimated and examined in sensitivity analyses. All cost outcomes were discounted at 3.0% annually. RESULTS: Total costs per successfully treated patient were €22,377 for RAL, €26,629 for ATV/r, and €23,928 for DRV/r. These results were found to be robust in sensitivity analyses. DISCUSSION: RAL has the lowest cost per successfully treated patient when compared with DRV/r and ATV/r, each used in combination with FTC/TDF, for treatment-naive adults with HIV-1 infection in Spain. This economic evidence complements the clinical benefits of RAL reported in the ACTG 5257 clinical trial.

Active Surveillance versus Spontaneous Reporting for First-Line Antiretroviral Medicines in Namibia: A Cost-Utility Analysis.

INTRODUCTION: Active surveillance pharmacovigilance is a systematic approach to medicine safety assessment and health systems strengthening, but has not been widely implemented in low- and middle-income countries. This study aimed to assess the cost effectiveness of a national active surveillance pharmacovigilance system for highly active antiretroviral therapy (HAART) compared with the existing spontaneous reporting system in Namibia. METHODS: A cost-utility analysis from a governmental perspective compared active surveillance pharmacovigilance to spontaneous reporting. Data from a sentinel site active surveillance program in Namibia from August 2012 to April 2013 was projected to all HIV-infected adults initiating HAART in Namibia. Costs (pharmacovigilance program, HAART, adverse event [AE] treatment), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs, dollars/QALY) were evaluated. Analysis was completed for (i) cohort analysis: a single cohort beginning HAART in 1 year in Namibia followed over their remaining lifetime, and (ii) population analysis: patients continued to enter and leave care and treatment over 10 years. RESULTS: For the cohort analysis, totals were US$21,267,902 (2015 US dollars) and 116,224 QALYs for care and treatment under active surveillance pharmacovigilance versus US$15,257,381 and 116,122 QALYs for care and treatment under spontaneous reporting pharmacovigilance, resulting in an ICER of US$58,867/QALY for active surveillance compared with spontaneous reporting pharmacovigilance. The population analysis ICER was US$4989/QALY. Results were sensitive to quality of life associated with AEs. CONCLUSION: Active surveillance pharmacovigilance was projected to be highly cost effective to improve treatment for HIV in Namibia. Active surveillance pharmacovigilance may be valuable to improve lives of HIV patients and more efficiently allocate health resources in Namibia.

Impact of Pill Burden on Adherence, Risk of Hospitalization, and Viral Suppression in Patients with HIV Infection and AIDS Receiving Antiretroviral Therapy.

STUDY OBJECTIVE: To evaluate the impact of pill burden on outcomes in patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) receiving antiretroviral therapy (ART) as a single-tablet regimen (STR) or multiple-tablet regimen (MTR). DESIGN: Retrospective cohort study. DATA SOURCES: South Carolina Medicaid medical and pharmacy paid claims data were obtained from the South Carolina Revenue and Fiscal Affairs Office; laboratory data were obtained from the South Carolina Department of Health and Environmental Control. PATIENTS: A total of 2174 patients covered by South Carolina Medicaid who were dispensed a complete ART STR (580 patients) or MTR (1594 patients) lasting at least 60 days between January 1, 2006, and December 31, 2013. MEASUREMENTS AND MAIN RESULTS: Outcomes were ART adherence; risk of, time to, and total number of hospitalizations; and viral load suppression. Patients were followed from the index date (start date of their complete ART regimen) until the earliest date of one of the following: treatment discontinuation; treatment switch from MTR to STR, or vice versa; end of study period; last date of Medicaid eligibility; or death. Differences in outcomes were evaluated by using bivariate χ(2) and Wilcoxon rank sum tests, as well as multivariate regression models controlling for covariates measured during a 6-month baseline period. The STR and MTR cohorts were, on average, similar in terms of age at index date, Charlson Comorbidity Index score, sex, drug abuse, and mental health diagnoses, but they differed significantly in racial composition, index year of regimen, previous treatment, baseline viral load, and CD4 measures. The bivariate analysis revealed that the STR cohort was more adherent (p<0.0001), had a lower risk of hospitalization (p=0.0076), and had a higher proportion of patients with viral suppression (64.5% vs 49.5%, p<0.0001). In addition, multivariate regression models revealed that the STR cohort was more adherent and was associated with a lower risk of hospitalization (hazard ratio 0.71, 95% confidence interval 0.59-0.86), but no significant difference in viral load suppression was noted between the STR and MTR cohorts. CONCLUSION: The STR was associated with higher adherence rates and a lower risk of hospitalization (both in the adjusted and unadjusted analyses) in South Carolina Medicaid patients with HIV infection and AIDS. A higher proportion of patients in the STR cohort had viral suppression during the follow-up period in the unadjusted analysis compared with the MTR cohort; however, no significant difference in viral suppression was observed when controlling for adherence.

[Dual therapy as an alternative treatment in HIV pretreated patients: experience in a tertiary hospital]. / Biterapia como alternativa de tratamiento en los pacientes VIH pretratados: experiencia en un hospital de tercer nivel.

OBJECTIVE: Dual therapy regimen might be an effective alternative to prevent the occurrence of side effects and comorbidities associated with prolonged treatment with antiretroviral (ARV) and a way of simplification of antiretroviral therapy (ART) to improve adherence in certain patients. It also represents a potential treatment option for patients who have failed previous TAR. METHODS: The aim of the study is to describe the effectiveness, adherence and costs of dual therapy regimen used in pretreated HIV patients in tertiary hospital. RESULTS: Thirty-eight patients were studied (eight were excluded). Reasons for simplification to dual therapy were previous treatment toxicity (40%), simplification (36.67%) and virological rescue (20%). The dual therapy regimens most used were: IP/r + INSTIs (26.67%), IP/r + NRTIs (23.33%), IP/r + NNR-TIs (23.33%), IP/r+ CCR5 (16.66%) e INSTIs + NNRTIs (10%). ARV more used were darunavir/ritonavir (DRV/r) + raltegravir (23.33 %); DRV/r + lamivudine (20%) y DRV/r + etravirine (16.67 %). Adherence was 86.79% before switching to dual therapy and 96.27% after switching. The cost savings of switching to dual therapy of these patients was € 3,635.16. CONCLUSIONS: Dual therapy with IP/r might be an effective alternative to selected treatment experienced patients compared with conventional therapy.

Low-Cost Method to Monitor Patient Adherence to HIV Antiretroviral Therapy Using Multiplex Cathepsin Zymography.

Monitoring patient adherence to HIV antiretroviral therapy (ART) by patient survey is inherently error prone, justifying a need for objective, biological measures affordable in low-resource settings where HIV/AIDS epidemic is highest. In preliminary studies conducted in Ethiopia and South Africa, we observed loss of cysteine cathepsin activity in peripheral blood mononuclear cells of HIV-positive patients on ART. We optimized a rapid protocol for multiplex cathepsin zymography to quantify cysteine cathepsins, and prospectively enrolled 350 HIV-positive, ART-naïve adults attending the Themba Lethu Clinic, Johannesburg, South Africa, to test if suppressed cathepsin activity could be a biomarker of ART adherence (103 patients were included in final analysis). Poor adherence was defined as detectable viral load (>400 copies/ml) or simplified medication adherence questionnaire, 4-6 months after ART initiation. 86 % of patients with undetectable viral loads after 6 months were cathepsin negative, and cathepsin-positive patients were twice as likely to have detectable viral loads (RR 2.32 95 % CI 1.26-4.29). Together, this demonstrates proof of concept that multiplex cathepsin zymography may be an inexpensive, objective method to monitor patient adherence to ART. Low cost of this electrophoresis-based assay makes it a prime candidate for implementation in resource-limited settings.

Effects of combination antiretroviral therapies on the risk of myocardial infarction among HIV patients.

BACKGROUND: Cohort studies have demonstrated greater risk of myocardial infarction (MI) associated with specific antiretroviral use, while meta-analyses of randomized controlled trials (RCTs) have not. These differences may be due to inherent biases in the observational study design or to the limited duration of randomized trials. We conducted a new-user, active-comparator cohort study emulating an RCT comparing the initiation of several antiretrovirals as part of combination antiretroviral therapy (cART) and MI. METHODS: We included North Carolina (NC) Medicaid beneficiaries infected with human immunodeficiency virus between 2002 and 2008 who were previously untreated with cART. We compared hazard ratios (HRs) and 95% confidence intervals (CIs) of MI between abacavir and tenofovir recipients, and lopinavir-ritonavir or atazanavir recipients and nonnucleoside reverse transcriptase inhibitor (NNRTI) recipients. We adjusted for confounding through inverse probability weighting methods. RESULTS: There were 3481 NC Medicaid new cART recipients who contributed 6399 person-years and experienced 38 MI events. Receiving abacavir compared with tenofovir as part of cART was associated with an increased rate of MI (unadjusted HR = 2.70 [95% CI = 1.24-5.91]; adjusted HR = 2.05 [0.72-5.86]). Point estimates also suggest a relationship between receipt of atazanavir or lopinavir-ritonavir compared with an NNRTI and MI, although estimates were imprecise. CONCLUSIONS: We found an increased rate of MI among patients initiating abacavir compared with tenofovir, although the association was decreased after confounding adjustment. Without a very large prospective comparative clinical trial, a much larger observational study of patients initiating cART would be needed to better define this apparent association.

In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity.

Several studies have reported an increased incidence of auditory dysfunction among HIV/AIDS patients. We used auditory HEI-OC1 cells in cell viability, flow cytometry and caspases 3/7-activation studies to investigate the potential ototoxicity of fourteen HIV antiretroviral agents: Abacavir, AZT, Delavirdine, Didenosine, Efavirenz, Emtricitabine, Indinavir, Lamivudine, Nefinavir, Nevirapine, Tenofovir, Ritonavir, Stavudine and Zalcitabine, as well as combinations of these agents as used in the common anti-HIV cocktails Atripla™, Combivir™, Epzicom™, Trizivir™, and Truvada™. Our results suggested that most of the single assayed anti-HIV drugs are toxic for HEI-OC1 auditory cells. The cocktails, on the other hand, decreased auditory cells' viability with high significance, with the following severity gradient: Epzicom âˆ¼ Trizivir >> Atripla âˆ¼ Combivir > Truvada. Interestingly, our results suggest that Trizivir- and Epzicom-induced cell death would be mediated by a caspase-independent mechanism. l-Carnitine, a natural micronutrient known to protect HEI-OC1 cells against some ototoxic drugs as well as to decrease neuropathies associated with anti-HIV treatments, increased viability of cells treated with Lamivudine and Tenofovir as well as with the cocktail Atripla, but had only minor effects on cells treated with other drugs and drug combinations. Altogether, these results suggest that some frequently used anti-HIV agents could have deleterious effects on patients' hearing, and provide arguments in favor of additional studies aimed at elucidating the potential ototoxicity of current as well as future anti-HIV drugs.

Longitudinal lactate levels from routine point-of-care monitoring in adult Malawian antiretroviral therapy patients: associations with stavudine toxicities.

INTRODUCTION: Stavudine is still widely used in under-resourced settings such as Malawi due to its low price. It frequently causes peripheral neuropathy and lipodystrophy and increases the risk of lactic acidosis and other high lactate syndromes. METHODS: We studied the association of longitudinal lactate levels, obtained by routine, 3-monthly point-of-care monitoring, with peripheral neuropathy, lipodystrophy and high lactate syndromes in adult Malawians who were in the second year of stavudine containing antiretroviral therapy (ART). RESULTS: Point-of-care lactate measurements were feasible in a busy urban ART clinic. Of 1170 lactate levels collected from 253 patients over the course of one year, 487 (41.8%) were elevated (>2.2mg/dl), 58 (5.0%) were highly elevated (>3.5mg/dl). At least one elevated lactate level occurred in 210 (83.0%) of patients and sustained hyperlactatemia in 65 (26.4%). In random effects analyses lipodystrophy and peripheral neuropathy were associated with higher lactate levels. Only five patients developed high lactate syndromes (one lactic acidosis) of whom no preceding lactate measurements were available because events had started before enrolment. Lactate levels significantly decreased over time and no high lactate syndromes were observed after the 15th month on ART. CONCLUSION: Lipodystrophy and peripheral neuropathy were associated with higher lactate levels. Lactate levels decreased over time, coinciding with absence of new high lactate syndromes after the 15th month on ART.

Social isolation in HIV-infected patients according to subjective patient assessment and DEXA-confirmed severity of lipodystrophy.

This study was designed to investigate the persistence of lipodystrophy (LD)-related social distress and isolation in HIV-infected patients in the current era, according to confirmatory dual energy X-ray absorptiometry (DEXA) measurements. Cross-sectional interview data were collected from 168 HIV-positive adult patients taking more than 2 years of antiretroviral therapy (133 cases with LD diagnosed a mean of 7.2 years before; 35 without LD, controls). Mean time of HIV infection was 16.2 years (2.1-27.3), and the mean time of exposure to highly active antiretroviral therapy of 11.7 years (2.1-21.1). The presence and severity of LD, confirmed by DEXA measurements, correlated with social isolation through a validated scale, including avoidance of social relationships, sex, work, or sport activities. In comparison with control patients, social distress was observed for patients having moderate body changes. The significant correlation between LD and social isolation was irrespective of age, CD4+ count, HIV RNA level, AIDS diagnosis, time of HIV infection, anxiety, or depressive symptoms. These results confirm that patient assessment of LD is correlated with whole-body DEXA scan, and they highlight the role of LD as an independent cause of social isolation even after years of the diagnosis.