The "ART" of Linkage: Pre-Treatment Loss to Care after HIV Diagnosis at Two PEPFAR Sites in Durban, South Africa

BACKGROUND. Although loss to follow-up after antiretroviral therapy (ART) initiation is increasingly recognized, little is known about pre-treatment losses to care (PTLC) after an initial positive HIV test. Our objective was to determine PTLC in newly identified HIV-infected individuals in South Africa. METHODOLOGY/PRINCIPAL FINDINGS. We assembled the South African Test, Identify and Link (STIAL) Cohort of persons presenting for HIV testing at two sites offering HIV and CD4 count testing and HIV care in Durban, South Africa. We defined PTLC as failure to have a CD4 count within 8 weeks of HIV diagnosis. We performed multivariate analysis to identify factors associated with PTLC. From November 2006 to May 2007, of 712 persons who underwent HIV testing and received their test result, 454 (64%) were HIV-positive. Of those, 206 (45%) had PTLC. Infected patients were significantly more likely to have PTLC if they lived =10 kilometers from the testing center (RR=1.37; 95% CI: 1.11-1.71), had a history of tuberculosis treatment (RR=1.26; 95% CI: 1.00-1.58), or were referred for testing by a health care provider rather than self-referred (RR=1.61; 95% CI: 1.22-2.13). Patients with one, two or three of these risks for PTLC were 1.88, 2.50 and 3.84 times more likely to have PTLC compared to those with no risk factors. CONCLUSIONS/SIGNIFICANCE. Nearly half of HIV-infected persons at two high prevalence sites in Durban, South Africa, failed to have CD4 counts following HIV diagnosis. These high rates of pre-treatment loss to care highlight the urgent need to improve rates of linkage to HIV care after an initial positive HIV test.US National Institute of Allergy and Infectious Diseases (R01 AI058736, K24 AI062476, K23 AI068458); the Harvard University Center for AIDS Research (P30 AI42851); National Institutes of Health (K24 AR 02123); the Doris Duke Charitable Foundation (Clinical Scientist Development Award); the Harvard University Program on AID

The Cost-Effectiveness of Tuberculosis Preventive Therapy for HIV-Infected Individuals in Southern India: A Trial-Based Analysis

Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India.We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm(3), and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH).Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of $5,630. 6EH increased life expectancy by 0.8 months at an additional per person cost of$100 (incremental cost-effectiveness ratio (ICER) of $1,490/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of$55 (ICER of $3,120/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence.Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care

Cost-Effectiveness of HIV Testing Referral Strategies among Tuberculosis Patients in India

Background: Indian guidelines recommend routine referral for HIV testing of all tuberculosis (TB) patients in the nine states with the highest HIV prevalence, and selective referral for testing elsewhere. We assessed the clinical impact and cost-effectiveness of alternative HIV testing referral strategies among TB patients in India. Methods and Findings: We utilized a computer model of HIV and TB disease to project outcomes for patients with active TB in India. We compared life expectancy, cost, and cost-effectiveness for three HIV testing referral strategies: 1) selective referral for HIV testing of those with increased HIV risk, 2) routine referral of patients in the nine highest HIV prevalence states with selective referral elsewhere (current standard), and 3) routine referral of all patients for HIV testing. TB-related data were from the World Health Organization. HIV prevalence among TB patients was 9.0% in the highest prevalence states, 2.9% in the other states, and 4.9% overall. The selective referral strategy, beginning from age 33.50 years, had a projected discounted life expectancy of 16.88 years and a mean lifetime HIV/TB treatment cost of US$100. The current standard increased mean life expectancy to 16.90 years with additional per-person cost of US$10; the incremental cost-effectiveness ratio was US$650/year of life saved (YLS) compared to selective referral. Routine referral of all patients for HIV testing increased life expectancy to 16.91 years, with an incremental cost-effectiveness ratio of US$730/YLS compared to the current standard. For HIV-infected patients cured of TB, receiving antiretroviral therapy increased survival from 4.71 to 13.87 years. Results were most sensitive to the HIV prevalence and the cost of second-line antiretroviral therapy. Conclusions: Referral of all patients with active TB in India for HIV testing will be both effective and cost-effective. While effective implementation of this strategy would require investment, routine, voluntary HIV testing of TB patients in India should be recommended

Cost-Effectiveness of Preventing Loss to Follow-up in HIV Treatment Programs: A Côte d'Ivoire Appraisal

Based on data from West Africa, Elena Losina and colleagues predict that interventions to reduce dropout rates from HIV treatment programs (such as eliminating copayments) will be cost-effective

The Cost-Effectiveness of Tuberculosis Preventive Therapy for HIV-Infected Individuals in Southern India: A Trial-Based Analysis

Background: Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India.Methods: We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm3, and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH).Results: Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of 5,630 USD. 6EH increased life expectancy by 0.8 months at an additional per person cost of $100 (incremental cost-effectiveness ratio (ICER) of 1,490 USD/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of 55 USD (ICER of 3,120 USD/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence.Conclusions: Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care.</p

Multi-way sensitivity analysis of 6EH major toxicity, regimen completion, and efficacy

<p>. Major toxicity associated with 6EH, percent cohort completion of the regimen, and efficacy of the regimen are varied simultaneously. The solid line represents the point estimate of efficacy for the 6EH regimen as observed in the trial, i.e. a rate ratio of tuberculosis incidence of 0.35 compared to no IPT, varied over a range of percent cohort completion of the regimen and probability of major toxicity. The shaded area to the right of the line represents all values at which the 6EH regimen is cost-effective, based on 3x the GDP <i>per capita</i> of India. The hatched line represents the leftwards shift in the boundary of cost-effectiveness when the rate ratio of TB incidence with 6EH is 0.21 compared to no IPT, as calculated from the lower bound of the 95% confidence interval of the trial. The dotted line represents the rightwards shift in the boundary of cost-effectiveness when the relative risk of TB with 6EH is 0.50 compared to no IPT, as calculated from the upper bound of the 95% confidence interval of the trial. The diamond in the lower right corner represents the base case, trial-based scenario, where percent cohort completion is 100% and the probability of major toxicity is 0.0029. <b>6EH:</b> Six-month regimen of isoniazid plus ethambutol, <b>IPT</b>: Isoniazid-based Preventive Therapy, <b>GDP</b>: Gross Domestic Product.</p

Incremental cost-effectiveness of additional strategies for TB preventive therapy.

<p><b>TB</b>: Tuberculosis; <b>USD</b>: US Dollars; <b>YLS</b>: Years of life saved: <b>IPT</b>: Isoniazid-based preventive therapy; <b>6H</b>: Six-month regimen of isoniazid; <b>3RH</b>: Three-month regimen of isoniazid plus rifampin; <b>6EH</b>: Six-month regimen of isoniazid plus ethambutol; <b>36H</b>: Three-year regimen of isoniazid; <b>3RPTH</b>: Three-month regimen of isoniazid plus rifapentine.</p>*<p>The incremental cost-effectiveness ratios may not exactly match the ratios of lifetime cost and life expectancy reported in the table due to rounding.</p>a<p>Weakly dominated (more expensive but confers less clinical benefit than some combination of other strategies) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036001#pone.0036001-Gold1" target="_blank">[12]</a>.</p>b<p>Strongly dominated (more expensive but confers less clinical benefit than some other strategy) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036001#pone.0036001-Gold1" target="_blank">[12]</a>.</p

Model validation and 10-year outcomes for TB incidence and cost of 6EH and 36H compared to no IPT.

<p><b>TB</b>: Tuberculosis; <b>PY</b>: Person-Years; <b>USD</b>: US Dollars; <b>IPT</b>: Isoniazid-based TB preventive therapy; <b>6EH</b>: Six-month regimen of isoniazid plus ethambutol; <b>36H</b>: Three-year regimen of isoniazid.</p

Tornado diagram of one-way sensitivity analyses comparing the 36H regimen to the 6EH regimen

<p>. Selected model parameters are listed on the vertical axis, with the range examined in sensitivity analyses listed in parentheses. The horizontal axis demonstrates the impact of changes in the parameter values on the incremental cost-effectiveness ratios for the 36H regimen compared to 6EH regimen. The solid vertical line indicates the incremental cost-effectiveness ratio estimate ($3,120/YLS) of the base case, and the dashed vertical line indicates the suggested cost-effectiveness threshold ratio of$2,940/YLS (3x GDP India). Values in white in the center of the bars indicate the threshold value of each parameter at which the cost-effectiveness ratio for 36H compared to 6EH is equal to $2,940/YLS. For example, a total cost of$90 for the 36H regimen was assumed in the base case. The incremental cost-effectiveness ratio of 36H compared to 6EH was less than or equal to $2,940/YLS (i.e. cost-effective by international standards) when the cost of 36H was less than$70. <b>36H:</b> Thirty-six-month regime of isoniazid, <b>6EH</b>: Six-month regimen of isoniazid plus ethambutol, <b>YLS</b>: Year of Life Saved, <b>GDP</b>: Gross Domestic Product.</p