Particularities of Cancer Management in HIV+ patients. Clinical Case Kaposi’s Sarcoma-Visceral Form

1. Introduction

The HIV virus is a member of the Retroviridae family. Its provirus persists indefinitely within the host cell. It is a contagious virus that spreads via blood and bloodcontaminated items, unprotected sexual contact, and mother-to-child transmission. It is frequently associated with other co-infections such as HPV, HCV, HBV, HHV-8, and EBV. Patients with HIV have a greater chance of developing cancer than the general population. Kaposi sarcoma is a malignancy that arises in endothelium cells, and it is related with HIV infection in 95-98 percent of cases.

Despite the enhanced efficacy of antiviral treatment, HIV infection is still a major issue today. According to U.S. statistics from March 2021, over 1.2 million Americans and over 35 million individuals worldwide are infected with HIV, with a mortality rate of 314 per 100,000 population. It is frequently linked to illnesses such as Human papillomavirus, Hepatitis B and C viruses, and Epstein-Barr virus (1).

The most common method of HIV transmission is unprotected sexual contact between gay males; a 2017 Kirby Institute report mentioned that 84% of all HIV-positive cases in Australia were transmitted sexually (2). The prevalence of HIV is higher among gay men than among heterosexual men, and the relationship between HIV infection and sexual behaviors is stigmatized by society. Low compliance with therapy and delayed medical visits may be related to this stigma. Historically, both homosexual and straight men, as well as drug users, were found to be a source of HIV transmission and a threat to the general population’s health (3).

As members of an HIV-affected community, both HIV-positive and HIV-negative gay males were subject to social stigma, according to a study by Broady et al. In Broady’s study there were 1760 individuals, 973 of them were HIVnegative, and 71.9% of the HIV-negative participants reported stigma via association (4).

Despite prevention efforts, homosexual and bisexual men have a higher chance of contracting HIV (5). In addition to a high vulnerability to infection, there is also a delay in presenting to the doctor at an early stage, which is why this patient category is at risk for developing cancers such as Kaposi sarcoma.

Individuals with HIV infection are more likely than the normal population to acquire both malignant tumors and non-oncological infections. According to version 1.2022 of the NCCN Guidelines, the most common malignancies in HIV-positive patients are Non-Hodgkin’s lymphoma (21%), Kaposi sarcoma (12%), lung cancer (11%) and anal cancer (10%). These patients are also exposed to other risk factors, such as smoking, drinking, and drug use. HIV infection is discovered in 1.1% of oncology patients; therefore, screening is essential, particularly for individuals with risk factors or those diagnosed with the aforementioned cancers (1).

Kaposi sarcoma is a cancer that arises in the endothelium cells, 95-98% of cases being linked to HIV infection. Moritz Kaposi, a pathologist, was the first to characterize the disease in 1872. When receiving the diagnosis, patients typically exhibit red or brown macules or papules on the skin or along the gastrointestinal tract (10-20% of cases) and the respiratory tract. This condition affects 30% of HIV-positive people, males being more likely than women to develop Kaposi sarcoma. Moreover, persons from the Mediterranean basin and Central and Eastern Europe are more susceptible to this disease. Iatrogenic or acquired immunosuppression is a substantial risk factor (6).

HIV is a key cofactor in the etiology of Kaposi sarcoma; however the widespread use of efficient antiretroviral therapies has recently led to a decline in Kaposi sarcoma incidence. Nonetheless, Kaposi sarcoma is the second most prevalent cancer among the HIV-positive population in the United States (7).

We herein discuss the case of a Caucasian patient who was treated with liposomal doxorubicin for Kaposi sarcoma and HIV infection. We have collaborated with an infectious disease specialist as part of a multidisciplinary team in order to treat HIV and prevent opportunistic infections in this patient.

2. Case Presentation

2.1. Diagnosis and work-up

In January 2022, a 44-year-old man was diagnosed with HIV infection. At that time, he had B symptoms, including asthenia and recurrent oral candidiasis. Blood tests revealed moderate normocytic normochromic anemia (Hb: 7.9 g/dl), a CD 4 count of 400 cells per microliter, and a viral load of one million copies per microliter. At that time he was taking one tablet of Doravirinum/ Lamivudine/Tenofovir Disoproxil. Also, he was taking Cinnarizine for insomnia. He did not have a history of cancer in his family, any known drug sensitivities, or work exposure to carcinogens. He was an avid smoker and an occasional alcohol consumer. He presented for the first time in February 2022 to a City Emergency Hospital Gastroenterology Department complaining of a recent onset of melena, nausea, halitosis, asthenia, and fatigability. Severe anemia (Hb: 6.2 g/dl), hypoalbuminemia (albumin: 2.5 g/dl), and hypoproteinemia have been detected in laboratory tests.

Endoscopy of the upper gastrointestinal tract revealed active bleeding from several sites. Several biopsies were conducted. The pathological analysis of the gastroscopy biopsies revealed that the patient had Kaposi sarcoma-visceral form (CD 31+, HHV8+, Ki 67 = 10%).

The endoscopic view of the lesions is presented in Figures 1A and B:

Figure 1 A and B. Endoscopic view of the hemorrhagic lesions found at gastric level

In April 2022, when he presented to our clinic, the patient’s performance status (PS) on the Eastern Cooperative Oncology Group (ECOG) scale was 2. As seen in Figures 2 and 3, the clinical examination revealed bleeding lesions in the oral cavity and pharynx, as well as purple nodular lesions on the trunk, limbs, and cervical region.

Fig. 2 Oral cavity at presentation

Head, chest, and abdominal computed tomography (CT) scans did not reveal any distant metastases.

Fig. 3 Trunk at presentation

2.1. Treatment

Since April 2022, the patient received liposomal doxorubicin 20 mg/ every two weeks, in accordance with the current standard of care of our department. Before beginning oncological treatment, the anemia and hypoalbuminemia were corrected with infusions of blood and human albumin. He was also administered hemostatic drugs to stop the bleeding, and he also began a new antiviral treatment prescribed by the infectious disease physician.

Figure 4 demonstrates a partial remission of the oral cavity lesions following two cycles of chemotherapy. The lesions ceased bleeding and the patient displayed no more symptoms.

Fig. 5. Oral lesions after four cycles of liposomal doxorubicin

He did not develop any hematological or gastroenterological toxicity during treatment.

After three rounds of therapy, the CD 4+ cell count increased from 400 to over 500 per microliter and the viral load was 50 copies per milliliter.

After the twelfth therapy cycle administered in October 2022, the patient’s ECOG performance status was assessed to be 0 and the disease was stable. We chose to discontinue oncological treatment till disease progression and to monitor the patient every three months. The patient was reintegrated into society and continued antiviral treatment. The last follow-up appointment was in January 2023, and the patient was clinically asymptomatic and diseasefree, with normal blood counts and metabolic evaluations.

2.3. Follow-up

He has completed his treatment at our Clinic. Every visit included a comprehensive clinical evaluation. From cycle to cycle, the signs and symptoms reduced, and by the eighth cycle, they had disappeared entirely. Every three months, he underwent head, thorax, and abdominal CT scans, and every six months, he underwent an upper gastrointestinal endoscopy. These investigations revealed no evidence of metastases or any new pathological alterations.

Over the entire period, the patient’s compliance with treatment programs and follow-up care was excellent.

The patient will continue to be assessed with a clinical exam, upper gastrointestinal endoscopy, and CT scan every three months. At present, the patient’s PFS reached more than ten months, and oncological treatment will be resumed if the disease progresses.

3. Discussion

HIV-positive patients are unique because they must deal with widespread stigma and a lack of social support. We herein report a case of a young male patient with Kaposi sarcoma who responded favorably to liposomal doxorubicin. Relative to other oncology patients, HIV-positive patients present extra treatment problems. In this case, the infectious disease specialist was included into the interdisciplinary team. According to NCCN guidelines, systemic therapy is preferred for patients with advanced illness. Hence, we opted for chemotherapy and maintained radiation therapy as a backup plan for refractory tumors. Medical literature describes liposomal doxorubicin or paclitaxel as initial treatment options. A randomized phase III patient trial comparing pegylated liposomal doxorubicin to doxorubicin/bleomycin/vincristine showed a 46% overall response to liposomal doxorubicin, compared to 25% for the control group (8).

Despite its benefit, liposomal doxorubicin is associated with the risk of cardiotoxicity (9, 10, 11). Paclitaxel, the alternative first-line therapy, has the same response rate and median progression-free survival as liposomal doxorubicin, but a higher incidence of grade 3 to 5 toxicity. In a randomized trial 73 patients with advanced HIVpositive Kaposi sarcoma received either paclitaxel 100 mg/m2 every 2 weeks or liposomal doxorubicin 20 mg/m2 every 3 weeks, respectively. The response rates (56% vs 46%; P=0.49), median progression-free survival (17.5 months vs 12.2 months; P=0.66), and 2-year survival rates (79% vs 78%; P=0.75), were comparable between the two arms but somewhat more grade 3 to 5 toxicity was observed for paclitaxel (84% vs 66%; P=0.077) (12).

Given the risk of neuropathy associated with Paclitaxel and the young age of our patient we opted for liposomal doxorubicin. The study of Cooley et al. concluded that pegylated liposomal doxorubicin is safe and effective in HIV positive patients with Kaposi sarcoma. Also, Shape et al. demonstrated in another randomized trial the benefit of monotherapy with pegylated liposomal doxorubicin in HIV positive patients with Kaposi sarcoma with response rates ranging from 46% to 77% (40, 41).

After a complete remission, it is important to take into consideration the fact that Kaposi sarcoma can recur. If the disease reappears, we must conduct a comprehensive physical, clinical, and paraclinical evaluation, including HIV viremia, a full blood count, a metabolic panel, and CT scans. Rechallenge with liposomal doxorubicin represents an option after progression, given that the patient tolerated the first-line therapy well and had a durable response (9 months to date) based on the patient’s response to the initial treatment. When choosing an oncologic treatment with liposomal doxorubicin, the maximum cumulative dose must be respected. Our patient has received 240 mg/m2 already. Another treatment option is pomalidomide (13). According to the NCCN guidelines, further lines of therapy may consist of bortezomib, gemcitabine, lenalidomide, nabpaclitaxel, or vinorelbine.

It is recommended to take photographs of the lesions at the time of diagnosis so that they can be compared in the event of a disease relapse. Surveillance included a physical examination, full blood count, and metabolic panel at each presentation, CT scans and HIV viremia level every three months, and upper gastrointestinal endoscopy every six months. Interestingly, in our patient, the CD 4 count was not decreased but on the other hand the viral load was elevated. At this time, we can not offer an explanation for this finding.

HIV-positive patients must undergo immunological reconstitution and take their antiviral medications. To offer the best care possible for HIV-positive individuals with Kaposi sarcoma, multidisciplinary collaboration between the oncologist and the infectious disease doctor is necessary.

Medical Literature

This type of cancer progresses much more rapidly in seropositive patients than in seronegative patients (6). The classifications for Kaposi sarcoma are classic (described by Moritz Kaposi), endemic (described in sub-Saharan Africa), iatrogenic (related with immunosuppressive medication), and epidemic (HIV-associated) (8, 14, 15).

According to an article written by de Moore et al., this type of patient may exhibit emotional distress and psychological burden (16). In Kaposi sarcoma, the prognostic factors are the extent of the tumor, the immunological status, and the severity of the systemic illness. Hence, a favorable prognosis is indicated by a skinlimited illness, a CD4 count larger than 200 cells/l, or the lack of opportunistic infections (17, 18). Even though our patient did not have a skin-limited condition, he did not have any opportunistic infections.

Low immunological state makes these individuals susceptible to opportunistic infections like as mycobacterium tuberculosis (3-16% of untreated HIV patients, according to Angel A. (19), CMV or Pneumocystis jirovecii, aspergillosis, and toxoplasma (1). All patients who exhibit any symptoms should be tested for these infections. Those with systemic diseases have the worse prognosis. A study indicated that the 3-year survival rate for these patients was 53%, compared to 80% to 88% for patients without systemic illness (8).

Differential diagnosis of the skin lesions is made with other infections, angiosarcoma and hemangiomas. Regardless of the typical aspect of the lesions, a biopsy is required for the diagnosis (14, 20).

In order to effectively treat patients, it is recommended to combine antiretroviral therapy and chemotherapy (21).

Local symptomatic therapy is beneficial for limited disease or cosmesis and includes intralesional chemotherapy with Vinblastine (injected directly into lesion), radiation therapy (for symptomatic disease that cannot be treated by intralesional chemotherapy or systemic therapy), and topical alitretinoin (9-cis retinoic acid-a topical gel for cutaneous lesions) (17, 13, 21, 22).

Patients with more than 25 skin lesions, significant edema, symptomatic visceral involvement, or those who have progressed while receiving antiviral medication may benefit from systemic therapy (17).

The preferred first-line systemic therapy is liposomal anthracyclines (doxorubicin), although according to the NCCN, Paclitaxel can be used if the patient is ineligible for the first drug. If a patient has heart illness, an irregular ECG, or has previously taken the maximal dose of liposomal doxorubicin for another tumor, he may not be eligible for this type of systemic treatment. The cardiologist who examined our patient determined that he had sinus rhythm, no ECG abnormalities, and an ejection fraction of 60%. Less hazardous than conventional anthracyclines, liposomal anthracyclines have a higher concentration in tumors. Paclitaxel, on the other hand, is more toxic than liposomal doxorubicin, although in some randomized trials it has demonstrated comparable survival rate benefits to liposomal anthracyclines. Remember that Paclitaxel requires premedication with glucocorticoids, which may worsen Kaposi sarcoma lesions, and that Paclitaxel has hepatic toxicity since it is processed by cytochrome P450 enzymes, similar to many antiretrovirals (17, 24).

The current standard for front line treatment for advanced HIV related Kaposi sarcoma is liposomal anthracyclines. Subsequently, according to Gill et al., (37) it is safe to administer paclitaxel 100 mg/2every two weeks to patients with advanced HIV related Kaposi sarcoma who experienced treatment failure of prior systemic therapy. If the patient does not respond to liposomal doxorubicin or Pacliatxel, further therapeutic options are further available: Pomalidomide (the preferred option), Bortezomib, Gemcitabine, Lenalidomide, nab-Pacitaxel and Vinorelbine (1).

The prognosis for these patients varies according to the disease’s stage. Depending on the status of the tumor, the immune system, and the systemic disease, there are a number of criteria that would classify people as highrisk. The NCCN classifies patients as high-risk if they have a tumor with edema or ulceration, an extensive oral or gastrointestinal sarcoma, or Kaposi sarcoma in organs other than lymph nodes. In addition, a T-cell count 150/microl is indicative of a poor prognosis. A history of opportunistic infections, fever, night sweats, involuntary weight loss, diarrhea lasting more than two weeks, and a Karnofsky Performance Status of less than 70, are considered high-risk features. The 5-year survival rate is 92% for local disease and 83% for extensive nodal disease. The 5-year survival rate has increased in recent years, particularly in the era of antiretroviral medication. In 1980, the five-year survival rate was 12.1%, as opposed to 86% in 1996, as indicated by Lodi et al. From January 1986 through December 2006, 9473 homosexual males, including 555 with Kaposi sarcoma, were included in CASCADE. 261 men diagnosed with Kaposi sarcoma died prior to 1996, 42 people died between 1996 and 2000, and 16 patients died between 2001 and 2006 (1, 24).

According to two studies, one realized by Carter et al. in 2010 and other by Crum-Cianflone et al. the same year, it was known that most cases of HIV-related Kaposi sarcoma tended to occur at low CD 4 counts (below 200 cells/3), but there were some cases of Kaposi sarcoma in HIV positive patients with a CD 4 count higher than 350 cells/ 3. In 1985-1990’s a total of 18% of patients diagnosed with HIV-related Kaposi sarcoma had a CD 4 count over 350 cells/3. In 2002-2008’s the precent increased to 35%. Each 50 cells/³ increase in CD 4 reduces the risk of cancer by 30% (42, 43).

Kaposi sarcoma is strongly associated with severe immunosuppression and an uncontrolled viral replication. Maurer et al., reported in 2006 some cases of patients with controlled viremia (lower than 300 copies/mL) and a CD 4 count more than 300 cells/³ with indolent Kaposi sarcoma. They had no eruptive cutaneous lesions or visceral involvement. According to a monocentric study from France, in aviremic patients, Kaposi sarcoma is more commonly indolent (44, 45, 46).

Nine unusual cases of persistent HIV-related Kaposi sarcoma occurring in patients with a CD 4 count higher than 300 cells/³ and a value of viral load lower than 300 copies/mL for at least two years have been previously reported. All the reported patients received antiretroviral therapy and had no history of opportunistic infections. They had a relatively indolent disease evolution (44).

The introduction of antiretroviral medication in 1996 has resulted in a decline in the incidence of Kaposi sarcoma, making this disease increasingly rare today (25). The risk of Kaposi sarcoma among HIV-positive individuals has dropped from 29.3% in 1996-2000 to 7.8% in 2000-2010. This is mostly attributable to the 1996 change of treatment recommendations, which advised the early start of antiretroviral therapy and removed the minimum threshold of CD 4+ cells required to initiate treatment. In addition, between 2000 and 2008, the usage of antiretrovirals among the U.S. population increased (26, 27).

The immunosuppression caused by HIV infection allows Kaposi sarcoma to develop in individuals who would have been asymptomatic carriers under normal circumstances. Originally, Kaposi sarcoma has been described in a population of promiscuous gay men (28). In the elderly, Kaposi sarcoma can be fatal; according to the stage and clinical presentation, the treatment consists in a combination of chemotherapy and radiotherapy. Xerosis is a common clinical finding in this population (24, 29).

There is a synergistic relationship between a high HIV viral load and an HHV-8 infection in HIV-positive Kaposi sarcoma patients. Usually, Kaposi sarcoma regresses after antiretroviral treatment. By immunosuppression and direct HHV-8 activation, elevated HIV levels can cause reactivation of HHV-8. Similarly, elevated amounts of HHV-8 can promote HIV replication. There is a correlation between HHV-8 load and CD 4 counts more than 200 cells per microliter. Latent HHV 8 persists in the cells of Kaposi sarcoma lesions as well as in leukocytes. The detection of herpesvirus DNA in leukocytes may indicate latent infection, whereas the detection of herpesvirus DNA in serum or plasma is typically indicative of disease. HHV-8 viral load may be effective for assessing therapy response in Kaposi sarcoma patients (30).

4. Conclusion

At present, Kaposi sarcoma becomes an uncommon pathology among HIV+ people in various parts of the world. Cases like the present one provides unique challenges for the oncologist. In HIV+ patients the oncological treatment, must be always combined with effective anti-HIV directed therapies.

Abbreviations

AIDS – acquired immunodeficiency syndrome

CT – computed tomography

EBV – Epstein-Barr Virus

ECOG – Eastern Cooperative Oncology Group

HBV – hepatitis B virus

HCV – hepatitis C virus

HIV – human immunodeficiency virus

HHV-8 – human herpesvirus 8

HPV – human papilomavirus

PFS – progression free survival

PS – performance status

Statements:

Authors’ contributions: FI wrote the manuscript, PE revised the text

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission

Conflict of interest: All authors declare having no competing interests associated with this publication.

Funding Sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

Informed Consent: The informed consent was obtained from the patient for publication and any accompanying images.

Ethical Approval: The treatment strategy was approved by the institutional/local tumor board (Colțea Clinic Hospital).

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