Persistent Kaposi sarcoma in the era of highly active antiretroviral therapy: characterizing the predictors of clinical response

Objectives: To evaluate the role of highly active antiretroviral therapy and chemotherapy on tumor response among persons with AIDS-related Kaposi sarcoma and identify factors associated with response in a clinic setting.

Design: Retrospective cohort.

Methods: One hundred and fourteen patients from two HIV clinics with a diagnosis of Kaposi sarcoma were identified via a clinical database. Records were reviewed to confirm Kaposi sarcoma diagnosis and abstract clinical and chemotherapy information. Demographics, laboratory values, and highly active antiretroviral therapy use were abstracted electronically. Cox's proportional hazards models identified predictors of Kaposi sarcoma improvement and resolution.

Results: Thirty-six months following Kaposi sarcoma diagnosis, the rate of improvement among 64 patients with confirmed Kaposi sarcoma was 77% and that of complete resolution was 51%. In univariate analyses, recent chemotherapy was associated with Kaposi sarcoma improvement, and recent HIV viral load and highly active antiretroviral therapy were associated with both improvement and resolution. No measured baseline characteristics (tumor stage, diagnosis year, CD4 T-cell count, HIV viral load, or prior highly active antiretroviral therapy history) or recent CD4 T-cell counts predicted improvement or resolution. In multivariate analyses, recent chemotherapy (hazard ratio 5.5, 95% confidence interval: 2.7-11.2, P < 0.001) and highly active antiretroviral therapy (hazard ratio 4.1, 95% confidence interval: 1.4-12.6, P = 0.01) were predictors of improvement; only recent highly active antiretroviral therapy was associated with resolution (hazard ratio 6.2, 95% confidence interval: 1.5-26.4, P = 0.01). Response was not associated with type of highly active antiretroviral therapy regimen (non nucleoside reverse transcriptase inhibitor based, protease inhibitor based, or ritonavir-boosted protease inhibitor based).

Conclusion: Highly active antiretroviral therapy and chemotherapy are important in clinical Kaposi sarcoma response. Despite widespread availability of these therapies, Kaposi sarcoma continues to be a clinical problem; only half the patients achieved complete resolution of disease. New therapeutic approaches are needed.

Introduction

Kaposi sarcoma remains the most common malignancy among persons with HIV despite dramatic declines in the incidence associated with highly active antiretroviral therapy (HAART) ^[1]. Prior to the introduction of HAART, treatment strategies for AIDS-related Kaposi sarcoma (AIDS-Kaposi sarcoma) had been mainly palliative, involving chemotherapy with low or short-term response ^[2]. HAART use among persons with AIDS-Kaposi sarcoma has been associated with improved survival and prolonged time to treatment failure ^[3-5]. Cases of complete Kaposi sarcoma resolution with HAART alone have been documented ^[6-10], but few studies have examined response to HAART in a clinical setting. Patients with advanced Kaposi sarcoma rarely respond to HAART alone, but HAART in combination with chemotherapy improves response rates to 50-82% ^[8,11-14]. Neither the relative roles of HAART and chemotherapy nor the predictors of response to both HAART and chemotherapy in persons with Kaposi sarcoma have been extensively described. Furthermore, evaluations of treatment with both HAART and chemotherapy in primary care settings, where adherence may be an issue, do not exist. Therefore, we sought to determine the role of HAART and chemotherapy on clinical response of Kaposi sarcoma during the 36 months following Kaposi sarcoma diagnosis among patients with AIDS-Kaposi sarcoma in routine primary care at two HIV clinics.

Methods

Study setting and participants

We examined all patients with a diagnosis of Kaposi sarcoma who were enrolled in the longitudinal study of HIV-infected patients at the University of Washington and Harborview Medical Center HIV clinics in Seattle, Washington, between 1 January 1996 and 31 December 2005. Patients in the University of Washington HIV Cohort receive primary care at University of Washington clinics, provide informed consent, and are followed until death or relocation from University of Washington. Information on sex, age, race, risk-group for HIV transmission, CD4 T-cell counts, HIV-1 plasma RNA levels (viral load), and antiretroviral treatment were obtained from the University of Washington HIV Information System (UWHIS), which captures longitudinal data on the University of Washington HIV Cohort from electronic medical records and other institutional data systems ^[15,16]. In addition, we reviewed medical charts to confirm Kaposi sarcoma diagnosis, classify Kaposi sarcoma tumor stage at diagnosis, obtain chemotherapy administration dates, and document changes in clinical appearance of Kaposi sarcoma. Kaposi sarcoma stage was defined according to AIDS clinical trials group (ACTG) tumor staging classification as T0 if the disease was confined to the skin and/or lymph nodes or oral involvement was confined to the hard palate, or T1 if there was pulmonary or gastrointestinal involvement, tumor-associated edema or ulceration, or extensive oral involvement ^[17]. We excluded patients who did not have clinically or histologically confirmed Kaposi sarcoma, were diagnosed with and/or received care for Kaposi sarcoma at institutions other than the University of Washington HIV clinics, or had all Kaposi sarcoma lesions removed.

Assessment of response

The interval between clinic visits varied in this population, but on average, patients are seen for routine care every 3-4 months ^[16]. We relied on clinicians to document changes in Kaposi sarcoma status in medical records. As this documentation was variable, we classified clinical response into three categories: no change/progression, improvement, and resolution. A patient was considered to have improvement if Kaposi sarcoma lesions improved without development of new lesions. Resolution of the disease was defined as having no evidence of lesions consistent with Kaposi sarcoma noted on physical examination. Disease progression or the absence of documentation of Kaposi sarcoma status in clinical notes was recorded as no change/progression. For this study, we performed separate evaluations for improvement and resolution.

Therapeutic regimens

More than 90% of the patients at the University of Washington clinics obtain their medications at the on-site pharmacy, where medications must be refilled monthly ^[18]. Information regarding medications dispensed outside University of Washington pharmacies are recorded in the chart review database and integrated in the UWHIS. We defined HAART use in a given month as prescription of three or more antiretroviral agents with at least one protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI). In addition, we were interested in determining whether specific HAART regimens, protease inhibitor based HAART regimens (protease inhibitor HAART) and regimens containing drugs found to be active against Kaposi sarcoma in vitro such as ritonavir (RTVB-HAART) were better predictors of clinical response than NNRTI-based HAART regimens (NNRTI-HAART) ^[19]. HAART adherence was determined by dividing the number of months on HAART by the total number of follow-up months after HAART initiation. 'Good adherence' was defined as at least 90% of HAART prescriptions filled as directed for the duration of observation. Chemotherapy use in a given month was defined as administration of chemotherapy during that month.

HIV treatment regimens are often dynamic; therefore, we determined the optimum treatment interval for prediction of improvement by comparing cumulative treatment time during various intervals between those who experienced improvement and those who did not. Persons with improvement were matched with those with no change/progression according to follow-up time. Comparisons for the periods 3, 6, 9, and 12 months prior to improvement were conducted using Wilcoxon's log-rank tests. Cumulative treatment months were dichotomized, as this summary measure appeared to best explain the treatment impact. Accordingly, when predicting improvement, recent HAART use was defined as 2 months or more of HAART in the past 3 months and recent chemotherapy use was defined as any chemotherapy in the past 3 months. The optimal treatment interval for prediction of resolution was determined in the same way; recent HAART use was defined as at least 5 months of HAART in the past 6 months and recent chemotherapy use was defined as any chemotherapy in the past 6 months.

Statistical methods

Kaplan-Meier survival analysis was used to estimate median time from Kaposi sarcoma diagnosis to first improvement and cumulative incidence of improvement 36 months after diagnosis; events were censored at the date of last visit, death, or 36 months following Kaposi sarcoma diagnosis. Univariate Cox's proportional hazards (Cox) models with time-varying covariates were used to quantify the risk for Kaposi sarcoma response with recent HAART and chemotherapy use and other possible predictive variables (age, Kaposi sarcoma stage, baseline CD4 T-cell count (≤200 vs. >200 cells/μl), baseline HIV viral load (<4 vs. ≥4 log₁₀ copies/ml), recent CD4 T-cell count, and recent HIV viral load). Recent CD4 T-cell count and HIV viral load were defined as the last recorded value within 12 months. Stepwise, backwards elimination was used to identify independent predictors of response. A P value less than 0.05 was considered statistically significant in multivariate analyses. A term indicating protease inhibitor-HAART use and RTVB-HAART use was added to the multivariate model to determine the additional effect of these regimens relative to NNRTI-HAART alone.

In a retrospective study such as ours, it is possible that patients were systematically prescribed specific treatment regimens based on characteristics of their HIV or Kaposi sarcoma disease. Thus, the indication for which regimen was prescribed could confound the perceived effect of that regimen on Kaposi sarcoma response. To determine whether confounding by indication was present, CD4 T-cell count and HIV viral load closest to HAART initiation within 3 months (at HAART initiation) was compared with an earlier value in the same participant 3-12 months prior to HAART initiation. McNemar's exact test was used to compare the proportion of patients with low CD4 T-cell count (≤200 cells/μl) and high HIV viral load (>5 log₁₀ copies/ml) at and prior to HAART initiation, and paired t-tests were used to compare mean changes in laboratory values.

To determine the impact of possible confounding by indication, we conducted an analysis using marginal structural models and compared it with a similar Cox's model. Marginal structural models are used to estimate the effect of a time-varying exposure on time-to-response outcomes when confounding by indication is present. Here, confounding by indication was considered to be likely, as the prescribing of antiretroviral therapy is commonly influenced by laboratory measures of immunosuppression such as CD4 T-cell count and HIV viral load, and HAART use impacts these same measures. The marginal structural model uses inverse probability weights to create a risk set where CD4 T-cell count and HIV viral load are no longer confounders by indication ^[20]. Given that marginal structural models are limited to nondynamic treatment regimens, we modeled the treatment for this model with the assumption that once a patient starts HAART, he/she remained on HAART. All analyses were performed with SAS statistical software, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA).

Results

Between January 1996 and December 2005, 114 patients were identified as having Kaposi sarcoma. After a careful review, 16 (14%) had an alternate diagnosis, 18 (16%) had insufficient information to confirm Kaposi sarcoma diagnosis, and 80 (70%) were confirmed to have Kaposi sarcoma. Of those with confirmed Kaposi sarcoma, 14 were diagnosed or treated elsewhere, two had their Kaposi sarcoma lesions completely excised, and the remaining 64 had sufficient information for inclusion in this study (Fig. 1).

Fig. 1

All patients were men; most were white (69%) and those who have sex with men (90%). Median age was 38 years (range 26-44). Forty-four (69%) had T0 disease, 20 (31%) had T1 disease, and 10 (16%) were on HAART in the 12 months prior to diagnosis. Median CD4 T-cell count at diagnosis was 40 cells/μl (interquartile range (IQR): 10-155), and median HIV viral load was 5.0 log₁₀ copies/ml (IQR: 4.1-5.4) (Table 1). Patients were followed up for a median of 6 months (range 1-36), with six deaths (9%) during follow-up for improvement, and a median of 16.5 months (range 2-36), with 15 deaths (23%) during follow-up for resolution.

Table 1

Treatment regimens

Improvement

Prior to improvement, 48 (75%) of 64 patients received HAART, constituting 319 (46%) of 695 person-months of follow-up. Thirty-eight (60%) persons received protease inhibitor-HAART (246 person-months) and 18 (28%) received RTVB-HAART (73 person-months) at some point during follow-up. The most common regimens were lamivudine-nelfinavir-zidovudine (19% of person-months) in 1996-1999, efavirenz-lamivudine-zidovudine (23%) in 2000-2003, and atazanavir-lamivudine-tenofovir-ritonavir (30%) in 2004-2006. Among those who started HAART, median time from Kaposi sarcoma diagnosis to HAART initiation was 1 month (range ≥12 months prior to 15 months after diagnosis), with a median duration of 4 months. Seven (15%) patients changed regimens two or more times during follow-up and 77% had good adherence.

Twenty-seven (42%) patients received chemotherapy, totaling 99 person-months. Liposomal doxorubicin was used the majority of the time (98%). The average time to start of chemotherapy was 3 months after Kaposi sarcoma diagnosis (range 0-32 months).

Resolution

During the time at risk for resolution, 53 (83%) patients received HAART, constituting 732 (59%) of 1238 person-months of follow-up. Forty-four (69%) persons received protease inhibitor-HAART (558 person-months) and 25 (39%) received RTVB-HAART (228 person-months) at some point during follow-up. The most common regimens were lamivudine-nelfinavir-stavudine (20% of person-months) in 1996-1999, efavirenz-lamivudine-zidovudine (19%) in 2000-2003, and atazanavir-lamivudine-tenofovir (34%) in 2004-2006. Among those who started HAART, median time from Kaposi sarcoma diagnosis to HAART initiation was 1 month (range ≥12 months prior to 19 months after diagnosis), with median duration of 11 months. Sixteen (30%) patients changed regimens at least twice during follow-up and 57% had good adherence, lower than that during the somewhat shorter periods prior to improvement.

Thirty-two (50%) patients received chemotherapy, totaling 256 person-months. Similar to the time prior to improvement, liposomal doxorubicin was used the majority of the time (96%). The average time to start chemotherapy was 6 months after Kaposi sarcoma diagnosis (range 0-32 months).

Response of Kaposi sarcoma to therapy

Improvement

During the 36 months following Kaposi sarcoma diagnosis, 42 patients experienced improvement in their Kaposi sarcoma disease with an overall estimated median time to first improvement of 9 months [95% confidence interval (CI): 4-11] and 3-year cumulative improvement probability of 0.77 (95% CI: 0.64-0.90) (Fig. 2). In an univariate analysis, none of the baseline clinical characteristics, stage, diagnosis year, CD4 T-cell count, HIV viral load, or prior HAART history was associated with improvement. However, risk of improvement was lower with higher levels of recent HIV viral load (hazard ratio = 0.7 for a log₁₀ copies/ml increase in HIV RNA levels, 95% CI: 0.6-0.9, P = 0.005). Recent CD4 T-cell count was not associated with persistent Kaposi sarcoma (P = 0.3). Both recent chemotherapy and HAART use were associated with improvement compared with those with no recent chemotherapy or HAART use, respectively (hazard ratio = 5.0, 95% CI: 2.5-10.0, P < 0.001 and hazard ratio = 2.6, 95% CI: 1.3-5.1, P = 0.006) (Table 2). Recent chemotherapy and HAART remained significant in multivariate analysis. The adjusted hazards for improvement was 4.1 times higher for those with recent HAART use compared with those with no recent HAART use (95% CI: 1.4-12.6, P = 0.01), and 5.5 times higher for those with recent chemotherapy compared with those with no recent chemotherapy (95% CI: 2.7-11.2, P < 0.001).

Fig. 2

Table 2

Resolution

The estimated median time to resolution was 33 months and 3-year cumulative resolution probability was 0.51 (95% CI: 0.34-0.68). None of the 19 patients with disease resolution had recurrence of the disease during the median 45 months of follow-up after resolution (range 0-111 months). Like Kaposi sarcoma improvement, the only clinical variable associated with resolution was recent HIV viral load (hazard ratio = 0.7, 95% CI: 0.5-1.0, P = 0.02). With regard to treatment, recent HAART use was associated with resolution (hazard ratio = 4.7, 95% CI: 1.4-15.8, P = 0.01), whereas chemotherapy was not (hazard ratio = 0.6, 95% CI: 0.2-1.7, P = 0.3). Only recent HAART use was statistically significant in multivariate analyses.

Comparison of highly active antiretroviral therapy regimens

The hazard ratio for improvement and resolution of Kaposi sarcoma associated with the different HAART regimens are shown in the multivariate models in Table 2. Among persons on HAART, those on RTVB-HAART were 2.7 times more likely to experience improvement than those on protease inhibitor-HAART, although this did not reach statistical significance (95% CI: 0.9-8.2, P = 0.08). Compared with those on NNRTI-HAART, risk for improvement did not differ for those on protease inhibitor-HAART (P = 0.12) or RTVB-HAART (P = 1.0). For Kaposi sarcoma resolution, neither protease inhibitor-HAART nor RTVB-HAART was significantly different than NNRTI-HAART (P = 0.6 and P = 0.5).

Indication for highly active antiretroviral therapy

The proportion of patients with low CD4 T-cell count was not different 3-12 months prior to compared with that at HAART initiation (P = 0.08); however, CD4 T-cell counts from the period prior to HAART initiation were significantly lower than counts at HAART initiation (mean decrease = 62 cells/μl, P = 0.01). Similarly, the proportion of patients with high HIV viral load (>5 log₁₀ copies/ml) was higher at HAART initiation than prior to HAART initiation (100 vs. 33%, P = 0.05), whereas there was no significant change in HIV viral load when considered as a continuous measure (P = 0.2).

Cox's models adjusting for chemotherapy, recent CD4 T-cell count, and recent HIV viral load and marginal structural models that account for confounding by indication with CD4 T-cell count and HIV viral load, chemotherapy, and baseline CD4 T-cell count and HIV viral load resulted in similar risk estimates for HAART for both improvement (Cox hazard ratio = 2.0, 95% CI: 0.9-4.6, and marginal structural hazard ratio = 1.7, 95% CI: 0.8-3.5) and resolution (Cox hazard ratio = 3.1, 95% CI: 0.4-26.1, and marginal structural HR = 3.9, 95% CI: 0.3-45.1).

Discussion

We evaluated the clinical response of AIDS-Kaposi sarcoma to HAART and chemotherapy among a large cohort of HIV patients in routine primary care and found that half completely resolved their disease within 36 months of diagnosis. This figure is similar to the observed resolution rates of 44-60% reported in smaller observational studies and clinical trials ^[21-24]. However, we found the median time to complete response (33 months) to be considerably longer than previously reported (6 months) ^{[7,9,10,23,25]}. Additionally, the median time to first improvement was 9 months, demonstrating that Kaposi sarcoma response is slow. Time to response may be longer in clinical settings compared with trials as treatment may not be started immediately, and clinicians may delay treatments such as cytotoxic chemotherapy in nonsevere patients. Taken together, our findings suggest that even in the era of extremely effective therapy for HIV infection and wide availability to chemotherapy, Kaposi sarcoma remains a persistent disease.

Both HAART and chemotherapy appear to have important roles in influencing the clinical course of AIDS-Kaposi sarcoma. Recent HAART use was the only factor associated with resolution and both HAART and chemotherapy were independently associated with improvement, suggesting that introduction of either HAART or chemotherapy can induce initial response to Kaposi sarcoma disease, whereas only HAART was associated with complete resolution of the disease.

A number of studies have attempted to identify predictors of Kaposi sarcoma response, but no factor has been consistently identified. CD4 T-cell count, HIV viral load, human herpesvirus-8 (HHV-8) DNA levels, or Kaposi sarcoma stage have each intermittently been associated with Kaposi sarcoma response ^{[6-8,11,14,21,22,24,26-28]}. Apart from recent HAART and chemotherapy use, the only other predictor of Kaposi sarcoma response identified in this study was low HIV viral load. This finding is consistent with multiple reports of Kaposi sarcoma improvement or resolution associated with significant decrease or undetectable HIV viral load ^[7,22,27]. It appears that controlling HIV viral load is essential for clinical improvement, disease resolution of Kaposi sarcoma, and perhaps decreased risk of relapse. Similar to other studies, we did not find an association between CD4 T-cell count and Kaposi sarcoma response, suggesting that suppression of HIV replication, and not immune reconstitution, may play a more important role in the resolution of Kaposi sarcoma ^{[14,22,27,29]}. Support for this hypothesis comes from several sources. First, in endemic areas, Kaposi sarcoma occurs in the absence of identifiable T-cell deficiency ^[30]. Second, it has been demonstrated that HIV induces lytic replication of HHV-8, and HIV Tat enhances the activity of HHV-8 genes involved in angiogenesis, proliferation, and viral replication ^[31].

Surprisingly, Kaposi sarcoma tumor stage was not associated with response in this study. Lack of relationship between disease stage and response to treatment is an unusual paradigm in cancer care, but is supported by other studies of Kaposi sarcoma treatment ^[11,14,27]. Only one study found Kaposi sarcoma tumor stage to be associated with the response, but the analysis was restricted to patients on HAART alone, without any systemic treatment ^[21]. Certain factors may have limited our ability to explore the Kaposi sarcoma tumor stage and response relationship. First, approximately 30% of patients had severe disease, but staging was performed only at diagnosis. It is conceivable that lesions could have progressed to more severe disease prior to treatment, though it is unlikely this would have affected treatment urgency or regimen. Second, we extrapolated staging based on clinical notes. It is possible that 'true' staging may have been confounded by failure to document extensive cutaneous or asymptomatic visceral disease in those scored with T0 Kaposi sarcoma. Alternatively, conventional ACTG tumor staging classification may not provide useful information with regard to tumor response in the setting of HAART and chemotherapy. Tumor extent continues to be an important predictor of survival ^[29], but none of the studies evaluating Kaposi sarcoma response in the presence of both HAART and chemotherapy found tumor stage associated with response ^{[11,14,27,28]}. One study noted a trend toward Kaposi sarcoma response for patients with T0 Kaposi sarcoma; however, this was only observed among antiretroviral naïve patients ^[27].

We found no differences in time to response among patients receiving NNRTI-HAART, protease inhibitor-HAART, or RTVB-HAART, similar to what has previously been described ^[7,27]. None of these regimens have been found to be more effective in the prevention of Kaposi sarcoma ^[32,33], but in-vitro models support a direct effect of specific antiretroviral agents on HHV-8 replication, production of HIV-1 Tat, and Kaposi sarcoma angiogenesis and apoptosis ^[19,34-38]. These studies support the concept that certain components of a HAART regimen may impact response of Kaposi sarcoma. Unfortunately, we lacked statistical power to evaluate the effects of specific antiretroviral therapy on Kaposi sarcoma due to the heterogeneity of treatment regimens prescribed and limited number of subjects. Additional studies on the differential impact of antiretroviral agents on HHV-8 replication and Kaposi sarcoma resolution deserves further study.

The current study has limitations. First, we relied on objective responses noted in clinical records for our outcome, as uniform staging was not completed for all patients at diagnosis or follow-up. A comparison of improvement of Kaposi sarcoma disease with other studies was difficult, as many studies used ACTG staging criteria for partial response, and most seemed as the best possible response, not time to first response. Second, 23% of patients died during follow-up. We suspect that death is not independent of response and therefore may have inflated our response rates. High death rates may bias the effect of treatment if treatment is associated with advanced HIV disease and death. However, we had insufficient statistical power to show that treatment-prescribing patterns changed prior to death, and therefore are unable to ascertain whether those who died were a poor representative of those censored at similar times. Finally, treatment effects may also be biased using Cox models because of confounding by indication. As the proportion of patients with high HIV viral load was higher at HAART initiation than in the preceding 3-12 months, clearly some of those on HAART may be more sick than those who are off and therefore are at a different risk of Kaposi sarcoma resolution. However, the treatment coefficients in the marginal structural models, which account for confounding by indication, differed little from those of the Cox model. Unfortunately, we were unable to identify a statistical method that adjusts for both confounding by indication and allows for dynamism in HIV therapy, and the application of such a model to retrospective studies in the future will permit more proper modeling of the scientific question.

Prior to HAART, few people experienced complete resolution of Kaposi sarcoma with chemotherapy alone and in those who responded, response was short lived ^[39-51]. Today, use of both HAART and chemotherapy is associated with a durable and complete resolution in half the patients studied. However, in sub-Saharan Africa, an area without widespread access to HAART and chemotherapy, Kaposi sarcoma continues to be a common malignancy, with an estimated 57 000 cases in 2002 ^[52-54]. Poor adherence and resulting drug resistance may also limit future treatment options with HAART. Kaposi sarcoma remains an important clinical problem today in both resource-poor and resource-rich settings for which new therapeutic approaches are urgently needed.

Acknowledgements

The authors thank Peggie Griffith for compiling the electronic medical files and Thomas Davis for assistance with data collection.

Sponsorship: This research was supported by NIH K23 AI54162 (C.C.) and K24 AI071113 (A.W.). Doris Duke Charitable Foundation Clinical Scientist Development Award, and Centers for AIDS Research.

This paper was presented in part at the 10th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies, North Bethesda, Maryland, 16-17 October 2006.