HIV This Week

When to start antiretroviral therapy in resource-limited settings.

Walensky RP, Wolf LL, Wood R, Fofana MO, Freedberg KA, Martinson NA, Paltiel AD, Anglaret X, Weinstein MC, Losina E; CEPAC (Cost-Effectiveness of Preventing AIDS Complications)-International Investigators. Ann Intern Med. 2009; 151:157-66.

The results of international clinical trials that are assessing when to initiate antiretroviral therapy will not be available for several years. The authors set out to inform HIV treatment decisions about the optimal CD4 threshold at which to initiate antiretroviral therapy in South Africa while awaiting the results of these trials by carrying out cost-effectiveness analysis of published data using a computer simulation model of HIV disease. The data were from randomized trials and observational cohorts in South Africa and the target population was HIV-infected patients in South Africa over a 5-year time horizon and over lifetime. The perspective was modified societal. The interventions considered were: no treatment, antiretroviral therapy initiated at a CD4 count less than 0.250 x 10(9) cells/L, and antiretroviral therapy initiated at a CD4 count less than 0.350 x 10(9) cells/L. The outcome measures were morbidity, mortality, life expectancy, medical costs, and cost-effectiveness. If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 x 10(9) cells/L would reduce severe opportunistic diseases by 22,000 to 221,000 and deaths by 25,000 to 253,000 during the next 5 years compared with ART initiation at 0.250 x 10(9) cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 10(9) cells/L. Compared with an initiation threshold of 0.250 x 10(9) cells/L, a threshold of 0.350 x 10(9) cells/L has an incremental cost-effectiveness ratio of $1200 per year of life saved. Initiating antiretroviral therapy at a CD4 count less than 0.350 x 10(9) cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%. This model does not consider the possible benefits of initiating antiretroviral therapy at a CD4 count greater than 0.350 x 10(9) cells/L or of reduced HIV transmission. Earlier initiation of antiretroviral therapy in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 x 10(9) cells/L, earlier than is currently recommended.

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Editors’ note: This cost-effectiveness analysis of 3 options (no treatment and treatment initiation thresholds of 250 and 350 CD4 cell counts) using a computer simulation to model HIV disease helps answer a critical question in the South African national context. What at the clinical outcomes and costs over the short-term (5 years) of different decisions on treatment initiation, taking into account the chance that the trials currently studying antiretroviral initiation will demonstrate a clinical benefit of antiretroviral treatment initiation at the 350 cell count level? Although randomised controlled trials, rather than models, are the gold standard for developing policy, models can help inform policy. Inadequate treatment capacity may exacerbate inequities in treatment access and this should be carefully monitored regardless of CD4 count entry criteria. Changes in the WHO treatment guidelines are likely to be announced in the coming months, provoking many countries which have not done so to consider how to strengthen their strategies for scale-up to universal access.

Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study.

Guiguet M, Boué F, Cadranel J, Lang JM, Rosenthal E, Costagliola D; on behalf of the Clinical Epidemiology Group of the FHDH-ANRS CO4 cohort. Lancet Oncol. 2009 Oct 7. [Epub ahead of print]

The relative roles of immunodeficiency, HIV viral load, and combination antiretroviral therapy in the onset of individual cancers have rarely been examined. The authors examined the effect of these factors on the risk of specific cancers in patients infected with HIV-1. They investigated the incidence of both AIDS-defining cancers (Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers (Hodgkin's lymphoma, lung cancer, liver cancer, and anal cancer) in 52 278 patients followed up in the French Hospital Database on HIV cohort during 1998-2006 (median follow-up 4.9 years, IQR 2.1-7.9; 255 353 person-years). They tested 78 models with different classifications of immunodeficiency, viral load, and combination antiretroviral therapy with Poisson regression. Current CD4 cell count was the most predictive risk factor for all malignancies apart from anal cancer. Compared with patients with CD4 count greater than 500 cells per muL, rate ratios ranged from 1.9 (95% CI 1.3-2.7) for CD4 counts 350-499 cells per muL to 25.2 (17.1-37.0) for counts less than 50 cells per muL for Kaposi's sarcoma (p<0.0001), from 1.3 (0.9-2.0) to 14.8 (9.7-22.6) for non-Hodgkin lymphoma (p<0.0001), from 1.2 (0.7-2.2) to 5.4 (2.4-12.1) for Hodgkin's lymphoma (p<0.0001), from 2.2 (1.3-3.6) to 8.5 (4.3-16.7) for lung cancer (p<0.0001), and from 2.0 (0.9-4.5) to 7.6 (2.7-20.8) for liver cancer (p<0.0001). For cervical cancer, they noted a strong effect of current CD4 (rate ratios 0.7 per log(2), 95% CI 0.6-0.8; p=0.0002). The risk of Kaposi's sarcoma and non-Hodgkin lymphoma increased for current plasma HIV RNA greater than 100 000 copies per mL compared with patients with controlled viral load (RR 3.1, 95% CI 2.3-4.2, p<0.0001; and 2.9, 2.1-3.9, p<0.0001, respectively), whereas combination antiretroviral therapy was independently associated with a decreased incidence (0.3, 0.2-0.4, p<0.0001; and 0.8, 0.6-1.0, p=0.07, respectively). The rate ratios of cervical cancer for those receiving combination antiretroviral therapy was 0.5 (0.3-0.9; p=0.03). The risk of anal cancer increased with the time during which the CD4 count was less than 200 cells per muL (1.3 per year, 1.2-1.5; p=0.0001), and viral load was greater than 100 000 copies per mL (1.2 per year, 1.1-1.4, p=0.005). Combination antiretroviral therapy would be most beneficial if it restores or maintains CD4 count above 500 cells per muL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation. Cancer-specific screening programmes need to be assessed in patients with HIV.

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Editors’ note: Patients with HIV have a higher risk than does the general population of both AIDS-defining and non-AIDS-defining cancers. However, since the introduction of antiretroviral treatment, the incidence of AIDS-defining cancers has decreased, whereas that of non-AIDS-defining cancers has increased. Both the size of this French cohort and its length of follow-up allowed investigation of seven specific cancers, finding that the risk of all of them increased with immunodeficiency. Among patients with Kaposi’s sarcoma, men who have sex with men are over-represented. Among patients with liver cancer and lung cancer, injecting drug users are over-represented. Antiretroviral treatment to keep CD4 counts above 500 cells combined with regular cervical-screening programmes for all HIV-positive women and early detection of anal cancer in men could help improve HIV-related cancer outcomes.