Malignancies in HIV/AIDS

From Epidemiology to Therapeutic Challenges

Paul G. Rubinstein; David M. Aboulafiac; Andrew Zloza

AIDS. 2014;28(4):453-465.

Abstract and Introduction

Abstract

The incidence of AIDS-defining cancers (ADCs) – Kaposi sarcoma, primary central nervous system lymphoma, non-Hodgkin lymphoma, and cervical cancer – although on the decline since shortly after the introduction of HAART, has continued to be greater even in treated HIV-infected persons than in the general population. Although the survival of newly infected people living with HIV/AIDS now rivals that of the general population, morbidity and mortality associated with non-AIDS-defining cancers (NADCs) such as lung, liver, anal, and melanoma are significant and also continue to rise. Increasing age (i.e. longevity) is the greatest risk factor for NADCs, but longevity alone is not sufficient to fully explain these trends in cancer epidemiology. In this review, we briefly review the epidemiology and etiology of cancers seen in HIV/AIDS, and in this context, discuss preclinical research and broad treatment considerations. Investigation of these considerations provides insight into why malignancies continue to be a major problem in the current era of HIV/AIDS care.

Introduction

In late 1995, the first generation of HIV protease inhibitors became commercially available. Within a few months, clinicians were combining these novel drugs with nucleoside and nonnucleoside reverse transcriptase inhibitors. The beneficial effects of what soon became known as HAART were immediate and profound. In just a few years, the number of cases of newly diagnosed AIDS, AIDS-related deaths, and AIDS-defining cancers (ADCs), had decreased by greater than 70%.^[1–3] However, even as AIDS-related mortality has continued to decline, the rate of new HIV infections has remained constant.^[4–6] Consequently, the number of people living with HIV/AIDS (PLWHA) has increased by a factor of four.^[4–6] Although HAART affords PLWHA a longer life expectancy, it also leaves them increasingly vulnerable to the same array of cancers associated with aging that are seen in the general population.^[7–12] These non-AIDS-defining cancers (NADCs) include those associated with viral infections [e.g. anal (human papillomavirus, HPV), liver (hepatitis C virus – HCV and hepatitis B virus – HBV), head and neck (HPV)] and those not associated with viral infections (e.g. lung and melanoma). In industrial nations, the number of cases of NADCs now equals or exceeds the number of cases of ADCs, and NADCs are a leading cause of mortality for PLWHA.^{[3,7–10,13–16]} Age and immune status, however, are insufficient to fully explain these trends in cancer risk. For PLWHA, even those with normal CD4⁺ T-cell counts, the risk for many NADCs remains greater than for their age-matched HIV-seronegative counterparts.^{[8–10,13,14]} Furthermore, compared with the general population, PLWHA present with more aggressive and advanced disease at the time of cancer diagnosis.^[17–20] These changes in cancer epidemiology are not well understood. We include preclinical research findings and discuss the epidemiology and etiology of both NADCs and ADCs. We also briefly examine cancer treatment in the context of HAART-chemotherapy interactions.

1 2 3 4 5

Next Section

Lippincott Williams & Wilkins

Table 1. Standard incidence ratios for common AIDS-defining and non-AIDS-defining cancers in the early and later HAART era and in the context of tumor-associated oncogenic viruses.
HIV-associated malignancies	SIR pre-HAART (1990–1995)	SIR early-HAART era (1996–2002)
ADCs
Kaposi sarcoma	22 100	3640
PCNSL	5000	>1020
Burkitt's lymphoma	52	49
DLBCL	64	29.6
All NHLs	79	22.6
Cervical carcinoma	4.2	5.3
NADCs
Hodgkin lymphoma	8.1	14
Anal carcinoma	18.3	33
Lung carcinoma	2.5	2.2–6.6
Head and neck carcinoma	1.2	1–4
Prostate cancer	N/A	4
Hepatocellular carcinoma	19	7–35
Melanoma	N/A	3
All NADCs	1.8	1.7–2

ADCs, AIDS-defining cancers; DLBCL, diffuse large B-cell lymphoma; EBV Epstein–Barr virus; HPV, human papillomavirus; N/A, not available; NADCs, non-AIDS-defining cancers; NHL, non-Hodgkin lymphoma; PCNSL, primary central nervous system lymphoma; SIR, standard incidence ratio.

Table 2. WHO classification of lymphoid malignancies associated with HIV infection.
Lymphoma type	Comments
Burkitt's lymphoma, Burkitt's-like lymphoma	Presents with a higher CD4⁺ T-cell count; 100% associated with cMYC translocation
Diffuse large B-cell lymphoma	Centroblastic 30% EBV [25,26]
Centroblastic immunoblastic (associated with PCNSL)	Immunoblastic 90% EBV and associated with primary CNS lymphoma [25,26]
Extranodal MALT lymphoma	Non-AIDS-defining cancer; rare
Peripheral T-cell lymphoma	Rare
Primary effusion/body cavity lymphoma	Rare; presents in patients in the late stages of HIV; associated 100% with HHV-8 and EBV [25,27]
Plasmablastic lymphoma of the oral cavity	Rare; associated with HHV-8 50% and EBV 50% [26]
Polymorphic B-cell lymphoma (PTLD-like)	Rare
Hodgkin lymphoma	Non-AIDS-defining lymphoma; may present in patients with elevated CD4⁺ T-cell count; EBV 80–100% [28]

DLBCL, diffuse large B-cell lymphoma; EBV, Epstein–Barr virus; HHV-8, human herpesvirus 8; MALT, marginal zone lymphoma of mucosaassociated lymphoid tissue; PCNSL, primary central nervous system lymphoma; PTLD, posttransplant lymphoproliferative disorder.

Table 3. Common AIDS-defining and non-AIDS-defining and tumor-associated oncogenic viruses.
HIV-associated malignancies	Associated oncogenic virus
Kaposi sarcoma	100% HHV-8 [53]
PCNSL	100% EBV [26]
Burkitt's lymphoma	20–40% EBV [26]
DLBCL	Centroblastic 30% EBV [26]
	Immunoblastic 90% EBV [26]
PEL	100% HHV-8 [27]
	100% EBV [25,27]
Plasmablastic	50% HHV-8 [25,26]
	50% EBV [25,26]
Cervical	100% HPV [53]
Hodgkin lymphoma	80–100% EBV [25,26]
Anal carcinoma	100% HPV [52]
Head and neck carcinoma	HPV [53]
	EBV [53]
Hepatocellular	HBV [53]
Carcinoma	HCV [53]

DLBCL, diffuse large B-cell lymphoma; EBV, Epstein–Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV-8, human herpesvirus 8; HPV, human papillomavirus; NADC, non-AIDS-defining cancer; NHL, non-Hodgkin lymphoma; PCNSL, primary central nervous system lymphoma; PEL, primary effusion lymphoma.

Table 4. Interactions between chemotherapeutics and antiretroviral agents.
Chemotherapeutic agents	P450 system responsible for metabolism	Antiretroviral inhibitor^a	Antiretroviral inducer^b	Associated cancers (being treated)
Vinblastine	CYP 3A4	Delavirdine,	Nivarapine	Hodgkin lymphoma
Vincristine		Ritonavir,	Efavirenz	ALL, NHL
		Amprenavir, Atazanavir,
		Indinavir
		Lopinavir
		Nelfinavir,
		Saquinavir
Paclitaxel	CYP 2C8	Same as above	Nivarapine	KS, breast, lung, cervical
Docetaxol	CYP 3A4		Efavirenz
Etoposide	CYP 3A4	Same as above		NHL, lung
	CYP 2E1
Ifosphamide	CYP 3A4	Efavirenz	Nivarapine	NHL, lung, breast, sarcoma
Cyclophosphamide	CYP 2C9	Amprenavir	Efavirenz
	CYP 2B6
Dacarbazine	CYP 2E1	Ritonavir		Hodgkin lymphoma

ALL, acute lymphocytic leukemia; CYP, cytochrome P450; KS, Kaposi sarcoma; NHL, non-Hodgkin lymphoma.
^aInhibitors increase the concentration of the active metabolite.
^bInducers decrease the concentration of the active metabolite.

Table 5. Major overlapping toxicities observed with HIV medications and chemotherapy.
Chemotherapy agent	Adverse events	HIV medication/class
Common with most chemotherapeutic classes. [i.e. anthracyclines, taxanes vinca alkaloids, platinums alkylating agents, camptothecans, etoposide, and antimetabolites (methotrexate and 5FU)]	Myelosuppression	Zidovudine
All taxanes; all vinca alkaloids; oxaliplatin; bortezomib	Neuropathy (motor and/or peripheral)	Didanosine; stavudine
Cisplatin	Nephrotoxicity	Tenofovir
Carboplatin		Indinavir
Common with most chemotherapeutic classes.	Nausea/vomiting	Protease inhibitors; zidovudine
Vinca alkaloids	Constipation
Common with most chemotherapeutic classes. (Chemotherapeutic agents that can be administered without any dose reductions in the setting of liver toxicity include cisplatin, gemcitabine, and bleomycin) [128]	Hepatotoxicity	Protease inhibitors; nucleoside and nonnucleoside reverse transcriptase inhibitors
Irinotecan	Diarrhea	Nelfinovir
Topotecan		Lopinavir
Fluorouracil

Table 6. General guidelines for the treatment of HIV-associated cancers.
Optimal treatment of patients with HIV-associated malignancies includes input from a multidisciplinary team consisting of a pharmacist, an infectious disease specialist, and a hematologist/oncologist. HIV medications can inhibit the Cyt p450 system, potentially augmenting toxicities by preventing chemotherapy metabolism (see Table 4 as a guide). Multiple overlapping toxicities are seen with HIV medications and chemotherapy agents (see Table 5 as a guide). Supportive care medications can also augment chemotherapy toxicities (i.e. azole antifungals and vincristine). Avoid the use of ritonavir when combined with vinblastine in the setting of Hodgkin's lymphoma. Rituximab offers substantial benefit when used with combination chemotherapy for treatment of CD20 aggressive B-cell lymphomas. Rituximab should not be withheld for patients with CD4⁺ cell counts less than 50 cells/ml. But care should be taken, as patients with low CD4⁺ T-cell counts are more prone to infectious complications. CD4⁺ T-cell counts can decrease during chemotherapy and/or in the setting of pelvic radiation. Thus, prophylaxis during therapy for opportunistic infections is often warranted despite a normal CD4⁺ T-cell count at therapy onset. Granulocyte colony-stimulating agents and antibiotic prophylaxis are strongly encouraged to minimize the effects of chemotherapyinduced neutropenia during the treatment of AIDS-related lymphomas.