HAART Resolves Life-Threatening Anemia in Women
"Impact of Highly Active Antiretroviral Therapy on Anemia and Relationship Between Anemia and Survival in a Large Cohort of HIV-Infected Women: Women's Interagency HIV Study"
--2000 HIV+ women followed in WIHS
--Among HIV-infected women who were not anemic at baseline, 47% became anemic by 3.5 years of follow-up
--Anemia is common in HIV-infected individuals, occurring in approximately 30% of those with asymptomatic HIV infection and in 75% to 80% of those with clinical AIDS
--Anemia is more common in women than in men, and its significance in terms of prognosis in the era of HAART has not yet been fully ascertained
--Anemia is an independent risk factor for decreased survival among HIV-infected women
--HAART therapy for as little as 6 months is associated with resolution of anemia.
--It is highly unlikely that anemia, per se, is the actual cause of death in these cases. Instead, anemia may serve as an indirect and surrogate marker for more advanced systemic illness. In this regard, anemia has also been associated with decreased survival times in other chronic illnesses, such as cancer.
--ritonavir, a PI, has been associated with decreased apoptosis of hematopoietic progenitors and direct stimulation of progenitor cell growth in vitro
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 37(2) 1 October 2004
Berhane, Kiros PhD*; Karim, Roksana MSc*; Cohen, Mardge H MD†; Masri-Lavine, Lena MSc*; Young, Mary MD‡; Anastos, Kathryn MD§; Augenbraun, Michael MD‖; Watts, D Heather MD¶; Levine, Alexandra M MD*
From the *Keck School of Medicine, University of Southern California, Los Angeles, CA; †Cook County Hospital, Chicago, IL; ‡Georgetown University, Washington, DC; §Montefiore Medical Center, Bronx, NY; ‖Maimonides Medical Center, Brooklyn, NY; and ¶National Institutes of Health, Rockville, MD.
The Women's Interagency HIV Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Institute of Child Health and Human Development, the National Institute of Drug Abuse, the National Institute of Dental Research, the Agency for Health Care Policy and Research, and the National Cancer Institute grants U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632, U01-AI-42590, and N01-AI-35161.
Background: Anemia is common in HIV-infected individuals and may be associated with decreased survival.
Objective: To ascertain the impact of highly active antiretroviral therapy (HAART) on anemia and the relationship between anemia and overall survival in HIV-infected women.
Methods: A prospective multicenter study of HIV-1 infection in women. Visits occurred every 6 months, including a standardized history, physical examination, and comprehensive laboratory evaluation. The setting was a university-affiliated clinic at 6 sites in the United States. Participants were 2056 HIV-infected women from the Women's Interagency HIV Study (WIHS). The outcome measure was anemia, defined as hemoglobin (Hb) <12 g/dL. Survival analysis was based on overall mortality during the follow-up period.
Results: At baseline, 36.7% of the HIV-infected women were anemic, with Hb levels <12 g/dL. At the end of the 3.5-year follow-up period, 47% of the women had been anemic during at least 1 study visit.
Before the introduction of HAART (visits 3 and 4, 1996), no significant trend was apparent in terms of the prevalence of anemia at each study visit (data not shown). Thereafter, however, women who used HAART for 2 or more intervals (at least 12 months) had a trend toward a lower likelihood of being anemic compared with those who received no HAART or those who used HAART for only 1 follow-up interval (6 months) (P = 0.12).
On multivariate analysis, the use of HAART was associated with resolution of anemia even when used for only 6 months (odds ratio [OR] = 1.45; P < 0.05). The likelihood of resolution of anemia was slightly higher for >=12 months of HAART use (OR = 1.47 [1.14, 1.91]; P = 0.004). Of interest, the use of AZT was associated with an inability to correct anemia (OR = 0.80 [0.64, 0.99]; P = 0.04).
In the multivariate model, a CD4 cell count <200 cells/μL (OR = 0.56; P < 0.001); HIV-1 RNA level >=50,000 copies/mL (OR = 0.65; P < 0.001), and mean corpuscular volume (MCV) value <80 fL (OR = 0.40; P < 0.001) were also associated with an inability to correct anemia.
Similarly, use of HAART for 12 months or more was associated with a protective effect against development of anemia (OR = 0.71; P < 0.001).
Among HIV-infected women, anemia was independently associated with decreased survival (hazard ratio [HR] = 2.58; P < 0.001). Other factors associated with decreased survival included a CD4 cell count <200 cells/μL (HR = 5.83; P < 0.001), HIV-1 RNA level >=50,000 copies/mL (HR = 2.12; P < 0.001), and clinical diagnosis of AIDS (HR = 2.83; P < 0.001).
Conclusions: Anemia is an independent risk factor for decreased survival among HIV-infected women. HAART therapy for as little as 6 months is associated with resolution of anemia.
Among the HIV-positive women who were free of anemia at baseline, several factors were independently associated with development of anemia over time, including low (<200 cells/μL) CD4 lymphocyte counts (OR = 1.98 [1.61, 2.42]; P < 0.001), low MCV levels <80 fL (OR = 4.19 [2.85, 6.15]; P < 0.001), and having clinically diagnosed AIDS (OR = 1.36 [1.13, 1.64]; P = 0.001). Being anemic during the prior time period was also significantly associated with still being anemic during the subsequent time period (OR = 6.99 [5.65, 8.64]; P < 0.001). A history of injection drug use at any time during follow-up was not associated with development of anemia (P = 0.38).
The number of women who were on HAART for at least 18 months was rather small at 18.7% (385 of 2056 participants), limiting the ability to examine an effect of HAART in this group. Of interest, the use of AZT either separately or as part of the antiretroviral regimen was significantly associated with increased odds of developing anemia (OR = 1.69 [1.42, 2.01]; P < 0.001).
The current report represents the largest prospective study yet conducted on the significance of anemia in HIV-infected women. Of importance, the development or persistence of anemia was shown to be independently and significantly associated with shorter survival. Other series have also noted a significant relationship between anemia and survival in HIV-infected individuals. In Moore et al's observational study, whereas receipt of erythropoietin was associated with resolution of anemia and decreased risk of death, correction of anemia by transfusions was associated with shorter survival. The study by Moore et al was conducted between July 1989 and December 1996, before the widespread use of HAART. In the study by Sullivan et al of 32,867 HIV-infected persons conducted before the HAART era, resolution of anemia was also associated with a prolongation in survival. Finally, the study by Semba et al9 of HIV-infected women noted a relationship between anemia and decreased survival. The reason for the poor prognostic impact of anemia in HIV disease remains speculative. It is highly unlikely that anemia, per se, is the actual cause of death in these cases. Instead, anemia may serve as an indirect and surrogate marker for more advanced systemic illness. In this regard, anemia has also been associated with decreased survival times in other chronic illnesses, such as cancer. Nonetheless, although the relationship between anemia and decreased survival in HIV infection may be indirect, all studies, including our own, have been consistent in noting this association. Further work is required to elucidate the precise mechanisms for this prognostically important association.
Other factors associated with decreased survival in our cohort included characteristics of more advanced HIV disease, such as a low CD4 lymphocyte count (<200 cells/μL), higher levels of HIV-1 RNA, and/or a diagnosis of an AIDS-defining clinical illness. Use of HAART for 6 months or longer was associated with a trend toward longer survival as has been reported by others.12 Of importance, the women in our cohort who initiated HAART earlier were more likely to include those who had more advanced HIV disease and were therefore at risk for a less optimal outcome.29 A total of 501 of 1054 HIV-infected women who initiated HAART in the WIHS had a history of clinical AIDS before HAART initiation. Our finding of a trend toward increased survival after short-term use of HAART (6 or 12 months) would thus indicate an advantage of HAART therapy in this group.
Our study has shown that the use of HAART for as little as 6 months is statistically associated with resolution of anemia, whereas longer use is associated with more profound improvements. The association of HAART with amelioration of the anemia of HIV infection has been reported by others.7,16,30 In a study of almost 7000 HIV-infected patients from across Europe, Mocroft and colleagues7 found that more prolonged HAART use was associated with a greater likelihood of correcting anemia. Thus, 65.5% of the cohort was anemic before the use of HAART, 53.2% was anemic after 6 months of HAART, and 46.2% was anemic after 12 months of HAART. The impact of increasing Hb levels on overall survival times after institution of HAART was not evaluated.7
Our findings regarding the effects of HAART on resolution of anemia and HAART's protective effect against development of anemia are unlikely to be caused by biases resulting from non-random missing data patterns.31 In a sensitivity analysis, we found that there was more loss to follow-up in the group that was anemic at baseline. From this observation, we conclude that our results remain valid, because the higher loss to follow-up occurred in the group that was more likely to stay anemic (baseline anemics). Thus, any bias that could result from this phenomenon on the effect of anemia on overall survival would be toward the null.
The mechanisms whereby HAART may be associated with correction of preexisting anemia are not yet fully understood. Most studies suggest that HIV-1 does not infect the hematopoietic progenitor.1,2,32 Nonetheless, abnormal growth of committed hematopoietic progenitor cells has been well described in HIV-infected persons.32 Further, HIV-1 infection of marrow stromal cells is sufficient to result in anemia and other cytopenias.33-35 A decrease in serum erythropoietin levels36; autoantibodies to erythropoietin37; or marrow suppression by opportunistic infections,38 tumors,39 or various medications40 may also contribute to the anemia commonly observed in HIV-infected persons. HAART may ameliorate many of these effects in an indirect manner simply by decreasing the HIV-1 viral burden.7,16,41 Additionally, however, Isgro et al42 have shown that HAART was associated with an increase in hematopoietic progenitor cell growth. Further, ritonavir, a PI, has been associated with decreased apoptosis of hematopoietic progenitors and direct stimulation of progenitor cell growth in vitro.5 These data would be consistent with our finding that HAART was associated with resolution of anemia.
Semba and colleagues9 have recently studied anemia in a cohort of HIV-infected and -uninfected women. Although the study design and patient population are similar to those of the WIHS, there are important differences in the modeling strategies, and thus in some of the conclusions drawn by each study. Semba et al9 examined risk factors for anemia in the pre-HAART and HAART eras, concluding that the risk of anemia was clearly decreased in the post-HAART era and that anemia was associated with a decrease in survival. By comparing the pre- and post-HAART eras alone, however, the effect of duration of HAART use on the development and/or resolution of anemia cannot be evaluated. Thus, we found that duration of HAART use was an important variable, with resolution of anemia seen after 6 months of HAART use and significant protection against development of anemia seen after 12 months of HAART use. Furthermore, we also examined those factors associated with the development or resolution of anemia separately. Additionally, in the Cox proportional hazards models, Semba et al9 used the baseline status of anemia as a risk factor instead of anemia status at any given visit. Because of the dynamic changes in Hb levels over time, we chose to consider anemia as a time-dependent covariate. Moreover, we chose to adjust for HAART use in the proportional hazards model. Neither the current study nor that of Semba and colleagues9 evaluated the specific causes of anemia in the 2 observational cohorts of women.
This study represents data from a large prospective cohort followed carefully over a 4-year period. Nonetheless, certain biases may have occurred. The HIV-positive women who received 3 or more intervals of HAART would have been those participants who had lived long enough to take the HAART for at least 18 months. On the other hand, HIV-positive women who began HAART early, thus having the opportunity for prolonged HAART use, would also be those participants with more advanced HIV disease at the time that HAART first became available. The first bias may have the potential of creating a tendency away from the null hypothesis, whereas the second has the potential of creating an inclination toward the null hypothesis. For this reason, the seemingly weak effect of HAART therapy on overall survival should be interpreted with caution. It is likely that the protective effects of HAART therapy may have been tempered by the fact that only those participants with more advanced HIV disease were given HAART at the time that it first became available. Further analyses will be conducted in the future to ascertain the role of long-term HAART use on anemia and survival times.
In conclusion, this study has confirmed the independent association between anemia and decreased survival among HIV-infected women. Further, we found that HAART therapy may be associated with correction of preexisting anemia after use for 6 months or more and with protection against development of anemia when used for 12 months or more. Further follow-up is required to determine the long-term effects of HAART therapy on anemia and survival.
Anemia is common in HIV-infected individuals, occurring in approximately 30% of those with asymptomatic HIV infection and in 75% to 80% of those with clinical AIDS. Anemia has been associated with decreased quality of life in HIV-infected persons4 and has also been associated with decreased survival in several studies, most of which are composed primarily of men. These studies have also demonstrated that recovery from anemia may be associated with a prolongation in survival. Thus, in an observational study, Moore and colleagues5 showed that administration of erythropoietin led to an increase in hemoglobin (Hb) levels and was associated with a significantly decreased hazard of death in a group of approximately 500 HIV-infected persons with anemia.
The presence of anemia in HIV-infected women is known to correlate with worsening HIV disease parameters, including a CD4 count <200 cells/μL, higher HIV-1 RNA levels in plasma, and a history of a clinical AIDS-defining illness. Recently, the use of highly active antiretroviral therapy (HAART) has been associated with improvements in immune function and significant declines in HIV-1 RNA levels. HAART has been widely used in the United States since 1996 and has led to a major decrease in AIDS-defining conditions, with significant prolongation in survival. HAART therapy consists of antiretroviral drugs from several classes, often including a protease inhibitor (PI). Of interest, ritonavir, a PI, has recently been shown to stimulate the growth of hematopoietic progenitors in vitro and to inhibit apoptosis of these progenitors. It is possible that the use of HAART might be associated with protection against anemia or correction of preexisting anemia as a result of HIV disease. A recent study by Mocroft and colleagues was consistent with this hypothesis, indicating that HAART therapy for 6 months or more was associated with a decreased likelihood of anemia. In a recent cohort of 66 HIV-infected patients, including 1 woman, Huang and colleagues demonstrated that the use of HAART was associated with an increase in white blood cells and platelets. Although an initial decrease in red blood cells occurred, Hb levels subsequently increased after 3 months of HAART use.
Anemia is more common in women than in men, and its significance in terms of prognosis in the era of HAART has not yet been fully ascertained. Therefore, in an attempt to evaluate the relationship between anemia and survival in HIV-infected women on HAART and/or other antiretroviral regimens, we studied 2056 HIV-infected women enrolled in the Women's Interagency HIV Study (WIHS). These women were followed over a period of approximately 4 years, from October 1994 through September 1998, in an attempt to ascertain the relationship between anemia and survival within the first 2 years of HAART use.
The WIHS is a multicenter prospective study of HIV-1 infection and associated diseases in women in the United States. From October 1994 through November 1995, 2056 HIV-1-infected women were enrolled in the WIHS at 6 sites throughout the United States (Los Angeles, CA; Washington, DC; San Francisco, CA; New York City/Bronx, NY; Brooklyn, NY; and Chicago, IL). Women were recruited from HIV clinics, street outreach, referral from other studies, and word of mouth. Informed consent was obtained from all participants as approved by the site-specific institutional review boards. WIHS methods and cohort characteristics have been described previously. Study participants were seen every 6 months and underwent a standardized history, physical examination, gynecologic examination, and blood tests at each of these visits. At a median of 3.5 years of follow-up, the retention rate of HIV-positive women was 80.4%, excluding deaths. During the 3.5-year follow-up period, a maximum of 8 study visits was possible for each participant. In fact, the median number of visits per participant was 6 (range: 1-8 visits). The majority of participants (1657 of 2056 participants [approximately 80%], excluding those who died) had their last visit after the widespread introduction and use of HAART. The presence of other intercurrent medical illnesses, pregnancy, menstrual and gynecologic history, and use of AIDS- and non-AIDS-related medications was recorded at each study visit. The WIHS is an observational study, however, and participants were not uniformly evaluated in terms of the potential cause(s) or specific types of therapy for anemia.