The Impact of HIV Status on Clinical Profile and Survival Among Patients With Diffuse Large B Cell Lymphoma in a Resource- Constrained Setting in the Haart Era

doi:10.21203/rs.3.rs-5297451/v1

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The Impact of HIV Status on Clinical Profile and Survival Among Patients With Diffuse Large B Cell Lymphoma in a Resource- Constrained Setting in the Haart Era

https://doi.org/10.21203/rs.3.rs-5297451/v1

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Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease encompassing a wide range of lymphomas, making diagnosis and treatment difficult. DLBCL accounts for half of non-Hodgkin lymphoma cases in people living with HIV/AIDS (PLWHA) and is the most common form of lymphoma in PLWHA. Even with the rollout of highly active antiretroviral therapy (HAART) and the availability of Rituximab, the treatment of DLBCL remains subpar in resource-constrained settings like Tanzania. This study aimed to identify differences in clinical profile and treatment outcomes between HIV-positive and HIV-negative DLBCL cases during the HAART era.

Methods: A retrospective review of medical charts of adults with a confirmed HIV infection status treated for DLBCL with chemotherapy +/- Rituximab and consolidation radiotherapy between January 2018 and December 2019 at Ocean Road Cancer Institute (ORCI) in Dar es salaam, Tanzania, was conducted. The clinical profile and overall survival for HIV-positive DLBCL were compared to that of HIV-negative DLBCL. Vital status at three years were determined. Survival functions were estimated using the Kaplan-Meier methodology. The equality of survival functions were assessed using Log-rank tests and Cox regression analysis to identify risk factors for mortality.

Results: One hundred and eleven eligible medical charts were identified. This was a cohort of black Africans with a median age of 46 (IQR: 18–81) with a 57.3% male gender distribution and 44% HIV prevalence. Overall survival (OS) at 12, 24, and 36 months for the population was 58%, 50%, and 38%, respectively, for the entire cohort. The clinical features for HIV-negative and HIV-positive DLBCL cases were similar except for the age at diagnosis, health insurance status, initial hemoglobin, functional status, and the use of salvage chemotherapy, whereby patients with HIV-positive DLBCL were more likely to be young, not have health insurance, have a low Karnofsky Performance score, have a low hemoglobin level, and be given salvage chemotherapy compared to HIV-negative DLBCL.

HIV status was not associated with a reduction in 3 years overall OS [adjusted hazard ratio (aHR)1.2, (95% CI 0.7–2.1)]. Consolidation radiotherapy use was not associated with a reduction in 3 years overall OS [adjusted hazard ratio (aHR)0.2, (95% CI 0.03–1.6]. Rituximab use was associated with a marginally statistically significant increase in mortality [adjusted hazard ratio (aHR)0.53, (95% CI 0.3–1.02)]. Risk factors of three years mortality was low hemoglobin level [aHR 0.46, (95% CI 0.3–0.8)] and high IPI score [aHR 0.46, (0.2–0.8)].

Conclusion: Patients with HIV-positive DLBCL were more likely to be young, not have health insurance, have a low Karnofsky Performance score, have a low hemoglobin level, and be given salvage chemotherapy compared to HIV-negative DLBCL. HIV status and consolidation radiotherapy were not predictors of OS in the entire cohort. Rituximab use was associated with a poor 3 years OS in Tanzania patients with DLBCL especially those with HIV positive DLBCL. Low hemoglobin levels and high IPI scores were predictors of mortality.

HIV

Diffuse Large B Cell Lymphoma

Tanzania

Oncology

Diffuse large B-cell lymphoma (DLBCL) accounts for 30–50% of non-Hodgkin lymphoma (NHL) cases in people living with human immunodeficiency syndrome (PLWH) (1)(2)(3). NHL constitutes about 80% of all lymphomas. B- cells are known to have functional diversity and propensity to transform into multiple pathways (4). Because of its functional diversity, it is a diverse group of clinically and pathologically diverse diseases. Over 30 different types of NHL have been identified, and the most prominent ones are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL)(5). DLBCL accounts for 50.9% of all NHL in Tanzania (6).

DLBCL has a male preponderance and a median age of 64 years. The overall incidence increases exponentially with age (2). DLBCL commonly presents with enlarged lymph nodes or rapidly growing mass along with B symptoms, which include fever, night sweats, and weight loss. The B symptoms can be seen in 30% of the patients. Indolent diseases are more likely to have bone marrow involvement, which can occur in as much as 50% of cases(7). Up to 40% of DLBCL cases are extranodal ( EN), with the gastrointestinal (GI) tract being the most common site(2).

The addition of the CD20 antibody, rituximab, during standard Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) chemotherapy has improved the 3-year overall survival rate by 10%(8).The use of rituximab in human immunodeficiency virus (HIV)-positive patients with DLBCL (HIV-positive-DLBCL) has coincided with improved outcomes in this group of patients and is recommended(9).

DLBCL is the most common HIV-associated lymphoma, comprising about 50% of all lymphomas seen in this group(10). The introduction of HAART has led to a reduction in the risk of acquiring NHL (11) and an improvement in the outcome of HIV-positive-DLBCL(12).

Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used for prognostication of DLBCL: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). Over 60 years of age, ECOG performance greater than 2, LDH elevated, Ann Arbor stage III/IV, and more than one extranodal involvement correlate with decreased overall survival (OS)(13).

This study aimed to evaluate the impact of HIV on the clinical characteristics and survival of patients with DLBCL in a resource-limited setting during the HAART era.

This retrospective cohort study was conducted at Muhimbili National Hospital (MNH) and the Ocean Road Cancer Institute (ORCI) in Dar es salaam, Tanzania. It included all patients with confirmed diagnoses of DLBCL and HIV status from January 2018 to December 2019. Patients without confirmed HIV status or with many missing data were excluded from the study.

This study was approved by the Muhimbili University of Health and Allied Science Ethical Committee board (Approval No. MUHAS-REC-12-2022-1489) and the Institutional Academics, Research, Publications, and Ethics Committee (IARPEC) of ORCI provided permission to conduct the study at ORCI.

Data were retrieved from the patient's medical charts, including an investigation of B symptoms routine, blood exams (hemoglobin, total and differential leukocyte counts, platelet count, and biochemical exams (liver function tests, serum lactate dehydrogenase (LDH), urea, creatinine, uric acid and serologic and HIV. The peripheral smear for abnormal/blast cells, β2 microglobulin, albumin, investigations for hepatitis B and C, bone marrow aspiration, and biopsy were not done as part of the staging procedure. The international prognostic index (IPI) and Ann Arbor stage were also extracted.

All patients were treated by systemic chemotherapy, mainly consisting of six cycles of the Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) regimen or Etoposide, Prednisone, Vincristine (Oncovin), Cyclophosphamide, Doxorubicin Hydrochloride and Rituximab (EPOACH-R). Patients with residual disease received local radiotherapy. Stem cell transplantation was not used for the patients who failed initial therapy. (14). A PET CT scan was not available to assess the treatment response.

The primary outcome was three years of overall survival (OS), defined as the duration from the date of completing treatment to the date of death or at the last follow-up. Variables with more than 10% missing data were not included. The multiple imputation method was used to replace missing data for variables with less than 10% missing data.

Shapiro–Wilk test was used to test if data was normally distributed. Normally distributed quantitative variables were summarized using mean and standard deviation, while non-normally distributed variables were summarized using median and interquartile ranges. Categorical variables were summarized using proportions. Student t-test was used to compare means, and the Mann–Whitney U test was used to compare medians. Survival was estimated using the Kaplan-Meier method. The prognostic value of the different variables for clinical outcome was calculated using a log-rank test in univariate analysis and the Cox proportional hazards regression model in multivariate analysis. A two-sided p-value < 0.05 was considered significant. The Statistical Package for the Social Sciences (SPSS version 15.0) software (Chicago, IL, USA) was used for data analysis.

Table 1

Clinical characteristics of patients with DLBCL by HIV status
		Entire cohort	HIV Positive	HIV Negative	P-Value
Age (Years)	Median(range)	46(19–81)	41(20–71)	58(19–81)	0.000
Gender	Male	64 (57.7)	26 (53.1)	38 (63.1)	0.4
	Female	47 (42.3)	23 (46.9)	24 (38.7)
Primary site	Neck	33(29.7)	16 (32.7)	17 (27.4)	0.06
	Chest	5 (4.5)	0 (0)	5 (8.1)
	Axilla	10 (9.0)	8 (16.3)	2 (3.2)
	Abdomen	13 (11.7)	6 (12.2)	7 (11.3)
	Disseminated	13 (11.7)	4 (8.2)	9 (14.5)
	Inguinal	14 (12.6)	4 (8.2)	10 (16.1)
	Others	23 (20.7)	11(22.4)	12 (29.4)
Health Insurance	Yes	29 (26.1)	7 (14.6)	22 (36.7)	0.01
	No	79 (73.6)	41 (85.4)	38 (63.3)
B Symptoms	Yes	48 (43.6)	28 (58.3)	26(41.9)	0.08
	No	62 (56.4)	20 (41.7)	36 (58.1)
Stage	I & II	71 (64.0)	30 (61.2)	41 (66.1)	0.59
	III & IV	40 (36.0)	19 (38.8)	21 (33.9)
KPS	< 80	91 (82.0)	44 (89.8)	47 (75.8)	0.057
	> 80	20 (18.0)	5 (10.2)	15 (24.2)
Extranodal disease	Yes	65 (59.1)	28 (58.3)	37 (59.7)	0.88
	No	45 (40.1)	20 (41.7)	25 (40.3)

About 130 files of medical charts of patients with NHL in the study period were reviewed, and 111 patients with DLBCL were recruited. This was a cohort of black Africans with a median age of 46 (IQR: 18–81) with a 57.3% male gender distribution and 44% HIV. The proportion of patients with DLBCL out of all patients with NHL was 84.6%. The neck was the most common primary site(29.7%). More patients with HIV-negative DLBCL had health insurance (36.7%) than patients with HIV-positive DLBCL (14.6%) (Table 1).

Table 2

A comparison of pathological characteristics of patients with DLBCL by HIV status
		Entire cohort	HIV Positive	HIV Negative	P-Value
Hemoglobin (g/dL)	Mean ± SD	10.3 ± 2.4	9.5 ± 2.2	10.9 ± 2.3	0.002
LDH (units/L)	Median	813	874	763	0.098
IPI score	Low risk	47 (41.1)	21 (41.7)	26 (40.7)	0.95
	Low Intermediate	34 (31.8)	15 (31.3)	19 (32.2)
	High Intermediate	14 (13.1)	7 (14.6)	7 (11.9)
	High risk	15 (14.0)	6 (112.5)	9 (15.3)

Patients with HIV-positive DLBCL had a lower mean hemoglobin level than those with HIV-negative DLBCL. Only 3 patients with HIV-DLBCL had baseline CD4 count levels (Table 2).

Table 3

A comparison of the management of patients with DLBCL by HIV status
		Entire cohort	HIV Positive	HIV Negative	P-Value
Initial Chemotherapy regimen	CHOP	46 (41.8)	23 (47.9)	23 (37.1)	0.25
	R-CHOP	64 (58.2)	25 (52.1)	39 (62.9)
Initial chemotherapy number of cycles	Median (IQR)	6(1–13)	5 (1–8)	6(1–13)	0.29
Salvage chemotherapy	Yes	5 (4.5)	0 (0)	5 (8.1)	0.04
	No	106 (95.5)	49 (100)	57 (91.9)
Rituximab	Yes	69 (62.7)	26 (54.2)	43 (69.9)	0.1
	No	41 (37.3)	22 (45.2)	19 (30.5)
Radiotherapy	Yes	9 (8.2)	3 (3.3)	6 (9.7)	0.5
	No	101 (92.8)	45 (93.8)	56 (90.3)
EQD2( Gy)	Mean ± SD	31.6 ± 7.9	26.6 ± 10.7	35.0 ± 3.4	0.1
Response	Complete	15 (13.5)	6(12.2)	9 (14.5)	0.34
	Partial	2 (1.8)	0 (0)	2 (3.2)
	No response	8 (7.2)	2 (4.1)	6 (9.7)
	Unknown	86 (77.5)	41(83.7)	45 (72.6)

There was more salvage chemotherapy use among patients with HIV-negative DLBCL (8.1%) than in patients with HIV-DLBCL (0%) (P = 0.04) (Table 3).

Number at risk

Cases

109

Overall survival (OS) at 12, 24, and 36 months for the population was 58%, 50%, and 38%, respectively, for the entire cohort.

Number at risk

HIV positive	48	21	19	12
HIV negative	62	35	24	18

The median overall survival of patients with HIV-positive DLBCL was 30 months, while that of HIV-negative DLBCL was 40 months (p = 0.45)( Fig. 1).

Number at risk

Low risk	42	28	21	15
Low intermediate	34	14	11	8
High intermediate	14	7	5	2
High risk	15	4	4	3

Patients with high IPI scores had poor overall survival compared to those with low IPI scores (p = 0.003) (Fig. 2).

Number at risk

No	40	21	19	9
Yes	69	34	28	20

In comparison to those who did not receive Rituximab, patients with DLBCL who received it had poor overall survival(p = 0.0035) (Fig. 3).

Number at risk

No	21	10	8	4
Yes	26	10	10	7

Patients with HIV-positive DLBCL who received Rituximab had a poorer survival rate than those who did not receive Rituximab(p = 0.00) (Fig. 4).

Number at risk

No	19	11	6	5
Yes	43	24	18	13

There was no difference in overall survival with the use of Rituximab in the HIV-negative DLBCL cohort. (p = 0.8) (Fig. 5).

Table 4

A summary of univariate and multivariate analysis
	Univariate analysis			Multivariate analysis
Variable	P-value	Crude HR	95% CI	P-value	Adjusted HR	95% CI
HIV status	0.5	1.2	0.7–2.1
Gender	0.8	0.9	0.5–1.6
Insurance status	0.4	1.3	0.7–2.6
Age	0.3	1	0.9-1
B symptoms	0.04	0.6	0.3–0.9
Stage	0.012	2	1.2–3.5
Hemoglobin (g/dl)	0.002	2.4	1.4–4.2	0.008	2.2	1.2–3.9
Extranodal disease	0.047	0.6	0.3-1.0
KPS	0.03	0.36	0.1–0.9
LDH	0.002	0.3	0.1–0.6
IPI score	0.001	2.6	1.5–4.6	0.012	2	1.2–3.7
Radiotherapy	0.07	0.2	0.02–1.1	0.14	0.22	0.03–1.6
Rituximab use	0.04	1.9	1.01–3.7	0.058	1.8	0.98–3.6

Univariate analysis summary

Patients without B symptoms had 40% less mortality risk ( p = 0.04). Patients with Ann Arbor stages III and IV were two times more likely to die compared to patients with Ann Arbor stages I and II (p = 0.012). Patients with hemoglobin levels less than ten g/dl were 2.4 more likely to die than those with hemoglobin levels of more than ten g/dl (p = 0.002). Patients without extranodal disease had 40% less mortality risk ( p = 0.04). Patients with a Karnofsky function score of 80–100 had 74% less mortality risk than those with a Karnofsky function score of less than 80 (p = 0.03). For every unit decrease in LDH level, there was 70% less mortality risk (p = 0.002). Patients with high-risk and high intermediate-risk IPI scores were 2.6 times more likely to die compared to those with low risk and low intermediate risk (p = 0.001). Patients who were given Rituximab were 1.8 times more likely to die compared to those who were not given (p = 0.058).

Multivariate analysis summary

Patients with high-risk and high intermediate-risk IPI scores were two times more likely to die compared to those with low-risk and low intermediate-risk (p = 0.012). Patients who were given Rituximab were 1.9 times more likely to die compared to those who were not given (p = 0.04). Patients with hemoglobin levels less than ten g/dl were 2.2 more likely to die than those with hemoglobin levels of more than ten g/dl (p = 0.008) (Table 4).

It is our belief that this is the first study in East Africa that analyzes the relationship between HIV status and survival among patients with DLBCL, considering the high burden of HIV infection in the region. In this study, we identified clinical and demographic differences between HIV-positive and HIV-negative DLBCL cases. The index study showed that 44% of all DLBCL patients were HIV positive. There is a significant variation in the prevalence of HIV infection among patients with DLBCL, ranging from 21% (2) to 81% (3), depending on the local prevalence of HIV infection in the general population.

The HIV-positive patients had a statistically significant lower age at diagnosis, with a median of 41 years, compared to 58 years for the HIV-negative cases (p < 0.000). The young age at presentation of HIV-positive DLBCL could be due to the interplay of viremia, immune dysregulation, and co-infection with oncogenic viruses that play a role in the pathogenesis of HIV-positive DLBCL. The lower age at diagnosis for HIV-positive DLBCL patients at 36–41 has been previously reported in several studies done in China, South Africa, Malawi, and Botswana (15) (16) (17) in comparison to higher median age at presentation of HIV negative DLBCL( 59–71 years)(3).

Health insurance coverage was higher for patients with HIV-negative DLBCL (36.7%) than those with HIV-positive DLBCL (14.6%). A study by Nguyen et al. in Vietnam also showed disparities in health insurance coverage among PLWHA. The data showed that the percentage of PLWHA who had health insurance was low, while the rate of PLWHA who couldn't afford health care services remained relatively high. Furthermore, the study demonstrated that many PLWHA were experiencing a lack of knowledge about health insurance and facing difficulties with accessibility, affordability, and use of health insurance (18).

Patients with HIV-positive DLBCL had a lower mean hemoglobin level in comparison to patients with HIV-negative DLBCL. Baseline anemia may be a consequence of bone marrow involvement by DLBCL, which may be a part of various factors causing anemia (19). Anemia is common in PWHA due to reduced bone marrow production and/or increased loss of peripheral red cells. HAART reduces the prevalence of anemia, with a reduction approaching 45% after 1 year of therapy (20).

Consolidation radiotherapy did not prolong overall survival in this study. The lack of survival benefit could be attributed to the lack of a PET CT scan to stage and evaluate the response to treatment. However, some studies suggest that consolidation radiotherapy is not essential in the rituximab era, especially if the interim PET CT scan shows a metabolic response has been attained due to high complete response rates with R-CHOP (21).

Patients who were not treated with Rituximab had a 47% lower risk of mortality than those who were given Rituximab, although the association was marginally significant (p = 0.058). Subgroup analysis showed that there was no significant difference in overall survival associated with the use of Rituximab among patients with HIV-negative DLBCL (Fig. 4); however, the use of Rituximab in the HIV-positive cohort resulted in poor overall survival (Fig. 5).AIDS Malignancy Consortium (AMC) trials have provided conflicting results concerning the benefit of rituximab(22). Similar findings were observed by Kaplan et al. among patients with HIV-positive NHL who were treated with R-CHOP while on HAART. Rituximab did improve overall survival. Treatment-related infectious deaths occurred in 14% of patients receiving R-CHOP compared with 2% in the CHOP group (P = 0.035). Of these deaths, 60% occurred in patients with CD4 counts less than 50/mm^3, although progressive disease was more common in those receiving CHOP alone (21.6%) compared with those who received R-CHOP (8.1%). Adding Rituximab to CHOP in patients with HIV-positive NHL may lead to better tumor responses. The advantages may be negated by increased infectious deaths, particularly for those with CD4 lymphocyte counts below 50/mm³ (23). Subsequent studies demonstrated that the combination of R-CHOP, R-CDE, R-EPOCH, or DA-EPOCH-R was beneficial, with an improvement in complete response rate (69–91%), in 2-year progression-free survival (59–69%) and in 2-year overall survival rate (64–75%), with a lower infectious death rate (< 10%)(24). Despite this evidence, the use of Rituximab in patients with CD4 lymphocyte counts below 50/mm3 remains controversial (24). The patients with HIV-positive DLBCL in this study may have succumbed to opportunistic infections after being given Rituximab. The CD4 counts of patients with HIV-positive DLBCL could not be retrieved in this study, and there was no documentation of whether they received infectious prophylaxis. However, a recent study done in Zimbabwe among patients with HIV-positive high-grade NHL with a median CD4 count of 173 cells/mm³ also failed to show the survival benefit of Rituximab despite having a median CD4 count of more than 50 cells/mm³ (22). The lack of overall survival benefit for patients with HIV-negative DLBCL could be attributed to the small sample size.

The median overall survival of patients who had HIV-positive DLBCL was 30 months, while that of patients with HIV-negative DLBCL was 40 months. However, this difference was not statistically significant (p-value 0.48). This finding is comparable to other studies, which showed almost similar two-year overall survival rates between HIV-positive and HIV-negative (25)(26)(27). During the pre-HAART era, outcomes were worse and heavily influenced by hematological toxicity (complete remission rates of roughly 50% and 5-year OS of approximately 28–48%), with a significant difference from HIV-positive patients(28). The therapy paradigm has significantly changed PLWHA with lymphomas in the HAART era. With improved viral load control, chemotherapy regimen management, and supportive care, survival is now approaching that of patients with HIV-negative NHL(28). Therefore, currently, the prognosis of HIV-positive DLBCL is determined by lymphoma features such as the international prognostic score (IPI), revised IPI, or age-adjusted IPI rather than HIV-specific factors (22). This study found a three-year OS rate of 50%, much lower than the US (70%), highlighting the challenges in managing DLBCL in resource-limited settings (27).

Study Limitations

This study had several limitations. Firstly, although it is the most extensive series reported in Tanzania thus far, it is limited by its small sample size. Secondly, due to its retrospective nature, clinical data of all the patients were not found in the clinical unit archives. Thirdly, we could not control for potential confounders like individual-level socioeconomic status because the data set lacked this information. Fourthly, most patients had no records of CD4 counts or viral loads. Fifthly, we could not assess the response due to the lack of a PET CT scan.

Patients with HIV-positive DLBCL were more likely to be young, not have health insurance, have a low Karnofsky Performance score, have a low hemoglobin level, and be given salvage chemotherapy compared to HIV-negative DLBCL. HIV status and consolidation radiotherapy were not predictors of overall survival in the entire cohort. The use of Rituximab resulted in poor survival, especially among patients with HIV-positive DLBCL. Low hemoglobin level and high IPI score were predictors of poor overall survival.

Conflict of Interest

The authors declare that the research was conducted without commercial or financial relationships that could create a conflict of interest.

Funding

There was no external source of funding for the study.

Acknowledgments

This article is based on N.A.M.'s Master of Medicine in Clinical Oncology dissertation submitted to Muhimbili University of Health and Allied Sciences.

Availability of supporting data

Supporting data is available upon request.

Authors’ contribution

Nur Antar Mabruk and Emmanuel L. Lugina are the first authors with equal contributions.

Agree to be accountable for all aspects of work: All the authors.

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No competing interests reported.

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The Impact of HIV Status on Clinical Profile and Survival Among Patients With Diffuse Large B Cell Lymphoma in a Resource- Constrained Setting in the Haart Era

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