Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults

Kaposi’s sarcoma was the first tumor to be described in association with HIV infection and is an AIDS-defining condition. It is also known as Kaposi's sarcoma-associated herpes virus (KSHV) as Herpes virus 8 (HHV8) is recognized as an essential and necessary factor in the pathogenesis of KS. Nonetheless, not all HHV-8-infected individuals will develop the disease. The abnormal cells of KS form purple, red, or brown patches, plaques or tumors on the skin. There is no universally accepted system for staging Kaposi's sarcoma. The most commonly used staging system for AIDS-related KS in adults is the AIDS Clinical Trial Group (ACTG) staging.

This review evaluated the effects of highly active antiretroviral therapy (HAART) and chemotherapy, or different chemotherapy regimens for severe or progressive Kaposi's sarcoma in HIV infected adults.

We found six randomised controlled trials and three observational studies that assessed the effects of HAART plus chemotherapy compared with HAART alone; HAART plus chemotherapy compared with HAART plus another chemotherapy regimen; and chemotherapy compared with chemotherapy in the time before HAART was available. Of the nine included studies, seven included patients with a mix of mild to moderate (T0) Kaposi's sarcoma and severe (T1) Kaposi's sarcoma. There was no universal definition for what severity of disease was considered chemotherapy-requiring. For this review, we only extracted data for 792 HIV infected adults with severe Kaposi's sarcoma disease.

The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, in choosing among different chemotherapy regimens, there was no observed difference between liposomal doxorubcin, liposomal daunorubicin, and paclitaxel. The overall quality of evidence in this review can be described as moderate.

Authors' conclusions: 

The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel.

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Background: 

Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence. However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.

Objectives: 

To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.

Selection criteria: 

Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.

Data collection and analysis: 

Two review authors assessed the studies independently and extracted outcome data. We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect. We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.

Main results: 

We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma. Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.

Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin, bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).

Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.

Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants). An additional non-randomised study showed a non-statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events.

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