This study is being done to determine if two different anti-cancer drugs, paclitaxel (PTX) and pegylated liposomal doxorubicin (PLD) have similar effects on treating Kaposi Sarcoma (KS) in people living with HIV (human immunodeficiency virus) in sub-Saharan Africa. Patients with HIV-related KS will receive either PTX or PLD once every 3 weeks for a total of six cycles.

Inclusion Criteria:

1. HIV-1 infection.

2. Histologically confirmed KS at any time prior to study entry, confirmed by an AIDS Malignancy Consortium (AMC)-certified pathologist.

3. Current stage T1 KS (irrespective of prior treatment with antiretroviral therapy (ART) OR

   Stage T0 KS that has progressed or not responded after a minimum of 12 weeks of treatment with ART. Participants with T0 KS must have either:

   • 20 or more skin and/or oral KS lesions, and/or
   • any number of lesions on exposed body areas that have an adverse effect on quality of life (e.g., stigmatization).

4. Men and women ≥ 18 years. Because no dosing or adverse event data are currently available on the use of PTX or PLD for AIDS-KS in persons <18 years of age, children are excluded from this study

5. Karnofsky performance status ≥ 60 (ECOG ≤ 2).

6. Echocardiogram or Multiple gated acquisition scanning (MUGA) showing an ejection fraction ≥ 50%.

7. Ability and willingness of participant or legal guardian to provide informed consent.

8. Participants may be ART-naïve or ART-experienced but must be able to receive an ART regimen considered likely to result in HIV suppression.

9. Measurable cutaneous KS, defined as follows:

   • When available, a minimum of five bi-dimensionally measurable KS cutaneous marker lesions.
   • If fewer than five bi-dimensionally measurable marker lesions are available, the total surface area of the marker lesion(s) must be ≥ 700mm2.

10. The following laboratory values obtained within 14 days prior to study entry:

    • Absolute Neutrophil Count ≥ 1000 cells/mm3.
    • Hemoglobin ≥ 8 g/dL (may be achieved with transfusion if clinically indicated, in the opinion of the investigator).
    • Platelet count ≥ 75,000/mm3.
    • ALT, AST, Alkaline phosphatase < 5 × upper limit of normal (ULN).
    • Total bilirubin: ≤ 1.5 × ULN, unless the participant is receiving an antiretroviral drug known to be associated with increased bilirubin, in which case the direct fraction should be ≤ 2 x the ULN.
    • Creatinine < institutional ULN OR estimated glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

11. Women of reproductive potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months), must have a negative pregnancy test done within 24 hours of initiating the protocol-specified chemotherapy medication.

12. Participants must agree to use two reliable forms of contraception simultaneously while receiving study protocol-specified medication and for 6 months after stopping the medication.

13. Adequate venous access.

14. No prior chemotherapy or use of systemic cytotoxic therapy agents.

15. Participant is able to understand and willing to sign a written informed consent document.

Exclusion Criteria:

1. Current acute, chronic, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy before study entry and/or is not clinically stable.
2. Serious illness necessitating hospitalization/systemic treatment within 14 days prior to study entry
3. Breastfeeding or pregnant women are excluded because of potential risks of cytotoxic chemotherapy to an unborn child or infant.
4. Known history of congestive heart failure and/or systolic ejection fraction < 50%.
5. Prior radiotherapy to KS indicator lesions
6. Prior or current immunotherapy
7. Any immunomodulator, HIV vaccine, live attenuated vaccine, other investigational vaccine within 30 days prior to study entry, excluding vaccines against COVID-19/SARS-CoV-2, which are permitted.
8. Known allergy/hypersensitivity to the study drug or its formulation
9. Any condition, including the presence of laboratory abnormalities, which in the opinion of the responsible investigator places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study.
10. Corticosteroid use at doses above those given for replacement therapy for adrenal insufficiency within the last 30 days prior to study entry.
11. Patients with psychiatric illness and/or social circumstances that would limit compliance with study requirements.