To our knowledge, this is the first report of CD4-specific mortality rates in HIV-infected adults with high CD4 count and no ART in West Africa.
Estimating CD4-specific rates requires longitudinal observational databases with repeated CD4 counts and standardized procedures. In sub-Saharan Africa, most of the large databases with longitudinal follow-up enroll HIV-infected patients at ART initiation.24 In untreated individuals, CD4 counts are often low at first contact25 and data on follow-up with high CD4 counts are scarce. Finally, most databases are rather program-based than research-oriented, meaning that data is recorded in real-life conditions, with rare CD4 count measurements and high rates of LTFU.26
We pooled data from ANRS-funded cohort studies in West Africa. In these studies, procedures, definitions, and data collection were standardized. Patients were followed free of charge, had systematic CD4 measurements every 6 months, and were systematically traced when they missed scheduled appointments.
CD4-specific mortality rates largely varied across cohorts. We censored follow-up at last contact in patients LTFU and at ART initiation in those who started ART. By doing so, we found the highest estimates of mortality within cohorts with the lowest rates of LTFU and in cohorts who were implemented during the pre-ART era and had the lowest rates of ART initiation. This strongly suggests that data censoring due to LTFU and ART initiation was informative and that mortality estimates are more accurate when rates of LTFU and ART initiation are low. As a consequence, in our study, true mortality figures are probably more accurately estimated in cohorts with the highest mortality rates and the lowest rates of LTFU and ART initiation; furthermore, in these cohorts with even low rates of LTFU and ART, mortality rates might be still underestimated because of informative censoring.
In our study, in the cohort with the lowest LTFU and ART initiation rates, mortality estimates were 5.0 per 100 person-years, 2.9 and 0.8 per 100 person-years in the 200–350, 350–500, and 500–650 CD4 cells per cubic millimeter strata, respectively. These rates are consistent with previous reports from Zimbabwe and South Africa.16,17 They are much higher than those reported by cohort collaborations from high-income countries.12,13 No formal comparison between settings is allowed, especially because our sample size is small and our confidence interval wide compared with those of large cohort collaborations from high-income countries. However, our findings strengthen the rationale for the 2010 WHO guidelines to increase the CD4 threshold for ART initiation from 200 cells per cubic millimeter to 350 cells per cubic millimeter in low-resource settings3 and suggest that the rationale for starting ART earlier than currently recommended might be even stronger in sub-Saharan Africa than in Europe or in North America. This also suggests that randomized trials assessing the benefits and risks of starting ART at high CD4 counts should carefully take into account the fact that mortality rates at high CD4 count might be different in high-resource as compared with low-resource settings.
Finally, our study confirms previous reports that many people are LTFU although waiting for ART, and suggestions by some authors that earlier initiation of ART may contribute to a better retention of patient in care.27
Our study has several limitations. The first limitation is its sample size. Yet our estimates are probably the best possible in the current context of obviously scarce data. Thus, there is clearly a need for large cohorts studies to be implemented in Africa, which would include patients with high CD4 counts and provide standardized follow-up before they initiate ART. These cohorts should ideally be multicountry and their funding should provide for a high level of data collection standardization, LTFU prevention, and morbidity documentation, conditions which are not always fulfilled in routine program databases.28,29
The second limitation is the extent of mortality underestimation. Our data suggest that LTFU and ART initiation probably led to underestimate true mortality rates in patients off ART through informative censoring, but the extent of this underestimation cannot be measured. LTFU may be a source of mortality misclassification, whereas ART initiation may be a source of both mortality and LTFU misclassification, as patients who start ART may be better retained into care than those who do not. The proportion of deaths among LTFU patients is unknown and may vary across CD4 strata. Available data on the outcomes of patients LTFU although on ART is increasing.30 Unfortunately, such data are scarce for individuals LTFU without ART with high CD4 counts.31,32 Even if recorded in the context of cohort studies, LTFU rates were similar or even higher than mortality rates, suggesting that even a low proportion of deaths among LTFU patients may have led to significantly underestimating mortality. We took into account informative censoring in the model estimating the CD4 count evolution,33 and by doing so we were able to accurately estimate the time spent within each CD4 strata. However, this did not allow us to adjust mortality rates with nonobserved events due to LTFU or initiation of ART.34
The third limitation is that we describe here crude mortality rates and not standardized mortality ratios. Therefore, we do not know how the mortality rates in patients with CD4 in the 2 strata >500 cells per cubic millimeter relate to the background population mortality.
The fourth limitation is that we did not address morbidity rates and causes of death in the present study. In fact, standardized morbidity data were recorded in only 2 of the 5 participating studies. Morbidity data from these 2 specific studies will be analyzed further.
Finally, our study included 80% of women. This percentage is higher than in the HIV-infected adult population in West Africa, thus limiting generalizability. Furthermore, 9% of the overall follow-up time was during pregnancy, which might influence data through both maternal mortality and the natural lowering of CD4 during pregnancy.35 The former might lead to overestimating mortality rates across the entire CD4 spectrum, whereas the latter might lead to misallocate some deaths to wrong CD4 strata.
In conclusion, mortality rates were substantial in our collaborative study conducted in West Africa in HIV-infected adults with more than 200 CD4 cells per cubic millimeter; all the more so as these mortality rates were probably underestimated because of informative censoring due to LTFU and ART initiation. We suggest that large multicountry cohorts including patients without ART with high CD4 counts should be implemented to better estimate the risk of early mortality in HIV-infected adults in sub-Saharan Africa. In such cohorts, underestimation of mortality due to informative censoring should be systematically discussed and the incidence of LTFU and ART initiation should be systematically provided when reporting CD4-specific rates of mortality.
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THE ANRS 12222 MORBIDITY/MORTALITY STUDY GROUP
Steering Comittee: X.A., Robert Colebunders, François Dabis, Joseph Drabo, Serge Eholié, D.G., Pierre-Marie Girard, Karine Lacombe, C.La., Vincent Le Moing, and C.Le.
Other representants of participating studies: Gérard Allou, C.A-B., D.A., Aida Benalycherif, Pierre de Beaudrap, Charlotte Boullé, P.C., Ali Coulibaly, Eric Delaporte, Lise Denoeud, Serge Diagbouga, D.K.E., Jean-François Etard, Sabrina Eymard-Duvernay, Patricia Fassinou, Isabelle Fournier-Nicolle, Hervé Hien, Charlotte Huet, I.K., Sinata Koulla-Shiro, Valériane Leroy, Olivier Marcy, Pierre Régis Martin, Nicolas Meda, E.M., A.M., Eitel Mpoudi-Ngolé, Philippe Msellati, Boubacar Nacro, Nicolas Nagot, Ibra Ndoye, Thérèse N'Dri-Yoman, A.O., Men Pagnaroat, Roger Salamon, Vonthanak Saphonn, Olivier Segeral, Catherine Seyler, Besigin Tonwe-Gold, Moussa Traore, Philippe Van de Perre, Ida Viho, Marcel Zannou.