Mitral Annular and Coronary Artery Calcification Are Associated with Mortality in HIV-Infected Individuals.

BACKGROUND: HIV infection increases cardiovascular risk. Coronary artery calcification (CAC) and mitral annular calcification (MAC) identify patients at risk for cardiovascular disease (CVD). The purpose of this study was to examine the association between MAC, CAC and mortality in HIV-infected individuals. METHODS AND RESULTS: We studied 152 asymptomatic HIV-infected individuals with transthoracic echocardiography (TTE) and computed tomography (CT). MAC was identified on TTE using standardized criteria. Presence of CAC, CAC score and CAC percentiles were determined using the modified Agatston criteria. Mortality data was obtained from the Social Security and National Death Indices (SSDI/NDI). The median age was 49 years; 87% were male. The median duration of HIV was 16 years; 84% took antiretroviral therapy; 64% had an undetectable viral load. CVD risk factors included hypertension (35%), smoking (62%) and dyslipidemia (35%). Twenty-five percent of individuals had MAC, and 42% had CAC. Over a median follow-up of 8 years, 11 subjects died. Subjects with CAC had significantly higher mortality compared to those with MAC only or no MAC. The Harrell's C-statistic of CAC was 0.66 and increased to 0.75 when MAC was added (p = 0.05). MAC, prior CVD, age and HIV viral load were independently associated with higher age- and gender-adjusted CAC percentiles in an adjusted model (p < 0.05 for all). CONCLUSION: In HIV patients, the presence of MAC, traditional risk factors and HIV viral load were independently associated with CAC. Presence of CAC and MAC may be useful in identifying HIV-infected individuals at higher risk for death.

Independent assessment of candidate HIV incidence assays on specimens in the CEPHIA repository.

OBJECTIVE: Cross-sectional HIV incidence surveillance, using assays that distinguish 'recent' from 'nonrecent' infections, has been hampered by inadequate performance and characterization of incidence assays. In this study, the Consortium for the Evaluation and Performance of HIV Incidence Assays presents results of the first independent evaluation of five incidence assays (BED, Limiting Antigen Avidity, Less-sensitive Vitros, Vitros Avidity and BioRad Avidity). DESIGN: A large repository of diverse specimens from HIV-positive patients was established, multiple assays were run on 2500 selected specimens, and data were analyzed to estimate assay characteristics relevant for incidence surveillance. METHODS: The mean duration of recent infection (MDRI, average time 'recent' while infected for less than some time cut-off T) was estimated from longitudinal data on seroconverters by regression. The false-recent rate (FRR, probability of testing 'recent' when infected for longer than T) was explored by measuring the proportions of 'recent' results in various subsets of patients. RESULTS: Assays continue to fail to attain the simultaneously large MDRI and small FRR demanded by existing performance guidelines. All assays produce high FRRs amongst virally suppressed patients (>40%), including elite controllers and treated patients. CONCLUSIONS: Results from this first independent evaluation provide valuable information about the current performance of assays, and suggest the need for further optimization. Variation of 'recent'/'nonrecent' thresholds and the use of multiple antibody-maturation assays, as well as other biomarkers, can now be explored, using the rich data generated by the Consortium for the Evaluation and Performance of HIV Incidence Assays. Consistently high FRRs amongst those virally suppressed suggest that viral load will be a particularly valuable supplementary marker.

CD4+ cell count at antiretroviral therapy initiation and economic restoration in rural Uganda.

OBJECTIVE: To determine whether earlier initiation of antiretroviral therapy (ART) is associated with better economic outcomes. DESIGN: Prospective cohort study of HIV-positive patients on ART in rural Uganda. METHODS: Patients initiating ART at a regional referral clinic in Uganda were enrolled in the Uganda AIDS Rural Treatment Outcomes study starting in 2005. Data on labor force participation and asset ownership were collected on a yearly basis, and CD4 cell counts were collected at pre-ART baseline. We fitted multivariable regression models to assess whether economic outcomes at baseline and in the 6 years following ART initiation varied by baseline CD4 cell count. RESULTS: Five hundred and five individuals, followed up to 6 years, formed the estimation sample. Participants initiating ART at CD4 cell count at least 200 cells/µl were 13 percentage points more likely to be working at baseline (P < 0.01, 95% confidence interval 0.06-0.21) than those initiating below this threshold. Those in the latter group achieved similar labor force participation rates within 1 year of initiating ART (P < 0.01 on the time indicators). Both groups had similar asset scores at baseline and demonstrated similar increases in asset scores over the 6 years of follow-up. CONCLUSION: ART helps participants initiating therapy at CD4 cell count below 200 cells/µl rejoin the labor force, though the findings for participants initiating with higher CD4 cell counts suggests that pretreatment declines in labor supply may be prevented altogether with earlier therapy. Baseline similarities in asset scores for those with early and advanced disease suggest that mechanisms other than morbidity may help drive the relationship between HIV infection and economic outcomes.

Association between U.S. state AIDS Drug Assistance Program (ADAP) features and HIV antiretroviral therapy initiation, 2001-2009.

BACKGROUND: U.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes. METHODS: We analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU). RESULTS: Among 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60-0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87-1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47-0.95). CONCLUSIONS: We found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed.

Food insecurity is associated with morbidity and patterns of healthcare utilization among HIV-infected individuals in a resource-poor setting.

OBJECTIVE: We undertook a longitudinal study in rural Uganda to understand the association of food insecurity with morbidity and patterns of healthcare utilization among HIV-infected individuals enrolled in an antiretroviral therapy program. DESIGN: Longitudinal cohort study. METHODS: Participants were enrolled from the Uganda AIDS Rural Treatment Outcomes cohort, and underwent quarterly structured interviews and blood draws. The primary predictor was food insecurity measured by the validated Household Food Insecurity Access Scale. Primary outcomes included health-related quality of life measured by the validated Medical Outcomes Study-HIV Physical Health Summary (PHS), incident self-reported opportunistic infections, number of hospitalizations, and missed clinic visits. To estimate model parameters, we used the method of generalized estimating equations, adjusting for sociodemographic and clinical variables. Explanatory variables were lagged by 3 months to strengthen causal interpretations. RESULTS: Beginning in May 2007, 458 persons were followed for a median of 2.07 years, and 40% were severely food insecure at baseline. Severe food insecurity was associated with worse PHS, opportunistic infections, and increased hospitalizations (results were similar in concurrent and lagged models). Mild/moderate food insecurity was associated with missed clinic visits in concurrent models, whereas in lagged models, severe food insecurity was associated with reduced odds of missed clinic visits. CONCLUSION: Based on the negative impact of food insecurity on morbidity and patterns of healthcare utilization among HIV-infected individuals, policies and programs that address food insecurity should be a critical component of HIV treatment programs worldwide.

Diminishing availability of publicly funded slots for antiretroviral initiation among HIV-infected ART-eligible patients in Uganda.

BACKGROUND: The impact of flat-line funding in the global scale up of antiretroviral therapy (ART) for HIV-infected patients in Africa has not yet been well described. METHODS: We evaluated ART-eligible patients and patients starting ART at a prototypical scale up ART clinic in Mbarara, Uganda between April 1, 2009 and May 14, 2010 where four stakeholders sponsor treatment - two PEPFAR implementing organizations, the Ugandan Ministry of Health - Global Fund (MOH-GF) and a private foundation named the Family Treatment Fund (FTF). We assessed temporal trends in the number of eligible patients, the number starting ART and tabulated the distribution of the stakeholders supporting ART initiation by month and quartile of time during this interval. We used survival analyses to assess changes in the rate of ART initiation over calendar time. FINDINGS: A total of 1309 patients who were eligible for ART made visits over the 14 month period of the study and of these 819 started ART. The median number of ART eligible patients each month was 88 (IQR: 74 to 115). By quartile of calendar time, PEPFAR and MOH sponsored 290, 192, 180, and 49 ART initiations whereas the FTF started 1, 2, 1 and 104 patients respectively. By May of 2010 (the last calendar month of observation) FTF sponsored 88% of all ART initiations. Becoming eligible for ART in the 3(rd) (HR = 0.58, 95% 0.45-0.74) and 4(th) quartiles (HR = 0.49, 95% CI: 0.36-0.65) was associated with delay in ART initiation compared to the first quartile in multivariable analyses. INTERPRETATION: During a period of flat line funding from multinational donors for ART programs, reductions in the number of ART initiations by public programs (i.e., PEPFAR and MOH-GF) and delays in ART initiation became apparent at the a large prototypical scale-up ART clinic in Uganda.

Retention in care among HIV-infected patients in resource-limited settings: emerging insights and new directions.

In resource-limited settings--where a massive scale-up of HIV services has occurred in the last 5 years--both understanding the extent of and improving retention in care presents special challenges. First, retention in care within the decentralizing network of services is likely higher than existing estimates that account only for retention in clinic, and therefore antiretroviral therapy services may be more effective than currently believed. Second, both magnitude and determinants of patient retention vary substantially and therefore encouraging the conduct of locally relevant epidemiology is needed to inform programmatic decisions. Third, socio-structural factors such as program characteristics, transportation, poverty, work/child care responsibilities, and social relations are the major determinants of retention in care, and therefore interventions to improve retention in care should focus on implementation strategies. Research to assess and improve retention in care for HIV-infected patients can be strengthened by incorporating novel methods such as sampling-based approaches and a causal analytic framework.

In vivo fitness cost of the M184V mutation in multidrug-resistant human immunodeficiency virus type 1 in the absence of lamivudine.

Lamivudine therapy selects for the M184V mutation. Although this mutation reduces the replicative capacity of human immunodeficiency virus in vitro, its impact on viral fitness in vivo has not been well defined. We used quantitative allele-specific PCR to precisely calculate the fitness differences between the mutated M184V virus and one that had reverted to the wild type in a cohort of patients by selectively interrupting reverse transcriptase inhibitor therapy, and we found that the M184V variants were consistently 4 to 8% less fit than the wild type in the absence of drug. After a lag phase of variable duration, wild-type variants emerged due to continued evolution of pol and back mutation rather than through emergence of an archived wild-type variant.

Sampling-based approaches to improve estimation of mortality among patient dropouts: experience from a large PEPFAR-funded program in Western Kenya.

BACKGROUND: Monitoring and evaluation (M&E) of HIV care and treatment programs is impacted by losses to follow-up (LTFU) in the patient population. The severity of this effect is undeniable but its extent unknown. Tracing all lost patients addresses this but census methods are not feasible in programs involving rapid scale-up of HIV treatment in the developing world. Sampling-based approaches and statistical adjustment are the only scaleable methods permitting accurate estimation of M&E indices. METHODOLOGY/PRINCIPAL FINDINGS: In a large antiretroviral therapy (ART) program in western Kenya, we assessed the impact of LTFU on estimating patient mortality among 8,977 adult clients of whom, 3,624 were LTFU. Overall, dropouts were more likely male (36.8% versus 33.7%; p = 0.003), and younger than non-dropouts (35.3 versus 35.7 years old; p = 0.020), with lower median CD4 count at enrollment (160 versus 189 cells/ml; p<0.001) and WHO stage 3-4 disease (47.5% versus 41.1%; p<0.001). Urban clinic clients were 75.0% of non-dropouts but 70.3% of dropouts (p<0.001). Of the 3,624 dropouts, 1,143 were sought and 621 had their vital status ascertained. Statistical techniques were used to adjust mortality estimates based on information obtained from located LTFU patients. Observed mortality estimates one year after enrollment were 1.7% (95% CI 1.3%-2.0%), revised to 2.8% (2.3%-3.1%) when deaths discovered through outreach were added and adjusted to 9.2% (7.8%-10.6%) and 9.9% (8.4%-11.5%) through statistical modeling depending on the method used. The estimates 12 months after ART initiation were 1.7% (1.3%-2.2%), 3.4% (2.9%-4.0%), 10.5% (8.7%-12.3%) and 10.7% (8.9%-12.6%) respectively. CONCLUSIONS/SIGNIFICANCE ABSTRACT: Assessment of the impact of LTFU is critical in program M&E as estimated mortality based on passive monitoring may underestimate true mortality by up to 80%. This bias can be ameliorated by tracing a sample of dropouts and statistically adjust the mortality estimates to properly evaluate and guide large HIV care and treatment programs.

Cost-effectiveness of HIV postexposure prophylaxis following sexual or injection drug exposure in 96 metropolitan areas in the United States.

OBJECTIVES: To evaluate the cost-effectiveness of HIV postexposure prophylaxis (PEP) following sexual or injection-related exposures in 96 metropolitan statistical areas in the United States (MSA). DESIGN: Empirical, model-based cost-effectiveness analysis. METHODS: Epidemiological and population size estimates from the literature were combined with information about the distribution of exposure types, PEP completion rate, proportion of source partners known to be HIV infected, and PEP program costs obtained from a feasibility study of PEP in San Francisco to estimate the cost-effectiveness of hypothetical PEP programs in each of the 96 MSA. The effectiveness of combination antiretroviral therapy following sexual or drug use-related exposures, which is presently not known, was assumed equal to the effectiveness of zidovudine monotherapy in the occupational setting. The main outcome measure was the cost-utility ratio, defined as the cost per quality-adjusted life year (QALY) saved by the PEP intervention. RESULTS: The cost-utility ratios for the 96 MSA ranged from 4137 dollars to 39,101 dollars per QALY saved; only two of the ratios exceeded 30,000 dollars per QALY saved. Combined across the 96 MSA, the hypothetical PEP programs would reach nearly 20,000 clients at a total cost of approximately 22 million dollars. The overall cost-utility ratio across MSA was 12,567 dollars per QALY saved. The majority of the HIV infections prevented by PEP were among men and women who reported receptive anal intercourse exposure. CONCLUSIONS: PEP following sexual or drug use-related exposures could be a cost-effective complement to existing HIV-prevention efforts in most MSA across the United States.

Cost-effectiveness of postexposure prophylaxis after sexual or injection-drug exposure to human immunodeficiency virus.

BACKGROUND: The cost-effectiveness of interventions that provide human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) to individuals after sexual or injection-drug use exposures depends on the distribution of exposure routes, prevalence of infection among source partners, adherence to PEP regimens, medical care costs, and prevailing epidemiologic contexts, among other factors. OBJECTIVE: To determine the cost-effectiveness of a comprehensive program to prevent HIV infection after sexual or injection-drug use exposure for 401 persons seeking PEP in an urban community. METHODS: We conducted a retrospective cost analysis to evaluate the cost of the PEP intervention, then combined this information with model-based effectiveness estimates to determine the PEP program's "cost-utility ratio," which is the ratio of net program costs to the total number of quality-adjusted life-years (QALYs) saved by the program. RESULTS: The average cost of the PEP regimen was $1222, and the total cost of the program was $450 970. The PEP program prevented an estimated 1.26 HIV infections, saved 11.74 QALYs, and averted $281 323 in future HIV-related medical care costs. The overall cost-utility ratio was $14 449 per QALY saved. When analysis was restricted to men reporting receptive anal intercourse, the savings in averted HIV-related medical care costs exceeded the cost of the program. The results were generally robust to changes in key parameter values but were sensitive to assumptions about the HIV transmission probability for receptive anal intercourse. CONCLUSIONS: For this study population, HIV PEP was cost-effective by conventional standards and cost-saving for persons seeking PEP after male-male receptive anal intercourse.