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Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa
Global Health Sciences Literature Digest
Published April 17, 2008
Journal Article

Moh R, Danel C, Messou E, Ouassa T, Gabillard D, Anzian A, et al. Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa. AIDS 2007 Nov 30;21(18):2483-91.

Objective

To estimate the incidence and risk factors of all causes of severe morbidity and mortality within the first months following early initiation of antiretroviral treatment (ART) in 792 HIV-infected adults in Abidjan, Côte d'Ivoire.

Study Design

Prospective cohort study with a median follow-up time of 8 months. In December 2002, the Trivacan multicenter randomized trial was launched in Abidjan.(1) The trial was designed in two phases. At inclusion, all patients started continuous ART and were followed under cohort procedures. After at least 6 months in the ART initiation phase, patients with undetectable viral load and CD4 cell count >350 cells/ml were randomized into the "ART interruptions strategies" phase. The criteria for being randomized had to be reached before 18 months of treatment. This paper reports on severe morbidity that occurred during the ART initiation phase of the Trivacan trial.

Setting

Abidjan, Côte d'Ivoire.

Participants

Participants were included if they met the following criteria: age ≥18 years, no past history of ART, CD4þ T-cell (CD4) cell count between 150 and 350 cells/µl or CD4 percentage between 12.5 and 20.0%, living in Abidjan and written informed consent.

Intervention

The procedures of the Trivacan trial have been described previously.(2,3) At enrollment, patients started either zidovudine (ZDV)-lamivudine-(3TC)-efavirenz or ZDV-3TC-indinavir/ritonavir. Cotrimoxazole was systematically given to all patients. Participants were attended by nurses, physicians, and social workers who were dedicated full-time to the study.

Primary Outcomes

Baseline characteristics, incidence of mortality, incidence of severe morbidity, the Kaplan-Meier probability of reaching virological success of ART, and the Kaplan-Meier probability of responding immunologically to ART were assessed. CD4 cell count and plasma HIV-1 RNA were measured every 3 months, and factors associated with death with severe morbidity were studied using a Cox proportional hazard regression analysis.

Results

Of the 792 patients included in this analysis, the majority had CD4 cell counts of >200 cells/µl (71%) and were at WHO stage 1 or 2 (64%). During follow-up, 370 patients were randomized in the Trivacan trial at 7 months, 155 (20%) at 10 months, 51 (6%) at 13 months, 28 (3.5%) at 16 months, and 188 (24%) were never randomized. Also, 18 patients died, including 8 with at least one documented episode of severe morbidity between inclusion and death, and 59 patients presented 65 episodes of severe morbidity. In patients with pre-ART CD4 cell count of <200, 200-350 and >350 cells/ml, incidence of mortality was 5.0 (95% confidence interval [CI] 2.6-8.7), 1.7 (95% CI 0.6-3.8) and 0.0 (95% CI 0.0-3.4]/100 person-years, and incidence of severe morbidity was 13.3 (95% CI, 9.0-19.1), 9.5 (95% CI, 6.2- 12.9) and 7.9 (95% CI, 3.4-15.5)/100 person-years, respectively. The most frequent diseases were invasive bacterial diseases (32/65 episodes, 49%) and tuberculosis (25/65 episodes, 38%). Both diseases followed the same curve of decreasing incidence over time. Patients who experienced severe morbidity had greater risks of mortality, virological failure and immunological failure. Other independent risk factors for mortality and/or severe morbidity were: at baseline, high viral load, advanced clinical stage, past history of tuberculosis, low BMI, low hemoglobin and low CD4 cell count; and during follow-up: low CD4 cell count and persistently detectable viral load.

Conclusions

The authors concluded that these data further reinforce the hypothesis that in this region ART should be started before the CD4 cell count drops below 350 cells/ml and that future studies should assess whether patients with low BMI, low hemoglobin, high viral load, WHO clinical stage 3, or past history of tuberculosis should start ART earlier.

Quality Rating

This study was of good quality. It followed cohort procedures with standardized documentation of all morbidity events and a low rate of loss to follow-up. Limitations were the following: 1) patients who reached criteria for ART success after 7 months were randomized into the Trivacan trial and therefore left the study. Thus, the follow-up of healthier patients was censored whereas the sicker patients remained in follow-up, which could have led to an overestimation of the mortality and morbidity rates after 7 months; and 2) patients were followed under trial conditions with all care free of charge. Thus, the rate of mortality would probably be higher if these patients had been followed-up in field conditions.

In Context

The patients in this study started ART with much more moderate levels of pre-ART immunosuppression compared with the vast majority of adults who have been initiated on ART in sub-Saharan Africa in recent years.(4,5,6,7) This study is the second time that an association between past history of tuberculosis and incident tuberculosis on ART has been reported in Cote d'Ivoire,(9) although such an association was not found in other studies conducted in South Africa.(7,8,9)

Programmatic Implications

The results of this study suggest that starting ART before the CD4 cell count drops below 350 cells/ml in HIV-infected adults in Côte d'Ivoire may prevent short-term mortality in patients on ART and may improve outcomes of short-term immunological and virological treatment by reducing the rate of severe morbidity.

References

  1. Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, Kanga C, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS1269trial): a randomized trial. Lancet 2006;367: 1981- 1989.
  2. Danel C, Moh R, Anzian A, Abo Y, Chenal H, Guehi C, et al. Tolerance and acceptability of an efavirenz-based regimen in 740 adults (Predominantly women) in West Africa. J Acquir Immune Defic Syndr 2006; 42:29-35.
  3. Moh R, Danel C, Sorho S, Sauvageot D, Anzian A, Minga A, et al. Haematological changes in adults receiving a zidovudine- containing HAART regimen in combination with cotrimoxazole in Cote d'Ivoire. Antivir Ther 2005; 10:615-624.
  4. Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, Miotti P, et al. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet 2006; 367:817-824.
  5. Etard JF, Ndiaye I, Thierry-Mieg M, Gueye NF, Gueye PM, Laniece I, et al. Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study. AIDS2006; 20:1181-1189.
  6. Seyler C, Anglaret X, Dakoury-Dogbo N, Messou E, Toure S, Danel C, et al. Medium-term survival, morbidity and immuno-virological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Cote d'Ivoire. Antivir Ther 2003;8:385- 393.
  7. Lawn SD, Myer L, Bekker LG, Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS2006; 20:1605-1612.
  8. Seyler C, Toure S, Messou E, Bonard D, Gabillard D, Anglaret X. Risk factors for active tuberculosis following antiretroviral treatment initiation in Abidjan. AmJ Respir Crit Care Med 2005; 172:123-127.
  9. Lawn SD, Badri M, Wood R. Risk factors for tuberculosis among HIV-infected patients receiving antiretroviral treatment. AmJ Respir Crit Care Med 2005; 172:1348; author reply 1348-1349.