E32 Malignancies in HIV patients
Worldwide, cancer is the third leading cause of death. Evolving demographic shift leads to the projection that cancer cases and deaths will double globally over the next 20-40 years. HIV infection poses an increased risk of cancers, the cause of which is multifactorial. HIV-associated immunosuppression compromises the ability to mount an immune response against oncogenic viruses and tumour antigens. The virus works synergistically with some oncogenic viruses to promote cancer growth in a weakened immune system. These viruses include Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV) or Herpesvirus 8 (HHV-8), Human Papillomavirus (HPV) and Hepatitis B (HBV) and C (HCV) viruses.[Box 32.1] Immune dysregulation, in particular increased levels of pro-inflammatory cytokines such as interleukins, also contribute to the development of certain cancers. With the advent of highly active antiretroviral therapy (HAART), people living with HIV/AIDS (PLWHA) now survive much longer, long enough for different cancers to develop. The entrenchment of modifiable risk factors (such as tobacco smoking, obesity and reduced physical activity) also contributes. Smoking, for example, is more common among PLWHA, putting them at increased risk of developing various smoking-related cancers.
Box 32.1. Viruses associated with HIV-related malignancies
|Malignancy||Virus (% of cancers associated with the virus)|
|Kaposi’s sarcoma||KSHV/HHV-8 (100%)|
|Primary central nervous system (CNS) lymphoma (PCNSL)||EBV (100%)|
|Primary effusion lymphoma (PEL)||EBV (70-90%)
|Burkitt lymphoma (BL)||EBV (<50%)|
|Diffuse large B-cell lymphoma (DLBCL), immunoblastic||EBV (>80%)|
|Leiomyosarcoma (in children)||EBV (~100%)|
|Hodgkin’s lymphoma||EBV (70-100%)|
|Multicentric Castleman’s disease||KSHV/HHV-8 (~100%)|
|Invasive cervical cancer||HPV (100%)|
|Anogenital cancers||HPV (100%)|
|Hepatocellular carcinoma (HCC)||HBV and HCV|
The epidemiology of cancers in HIV patients has significantly evolved over the past decade. Kaposi’s sarcoma, high grade B-cell non-Hodgkin’s lymphoma (NHL) and invasive cervical cancer are the 3 AIDS-defining cancers (ADCs). With the introduction of HAART, the incidence of AIDS-related cancers has fallen sharply, especially those associated with low CD4 counts. In contrast, international HIV cohort studies have consistently reported an increased risk for non-AIDS-defining cancers (NADCs). A retrospective analysis described the incidence of different cancers and risk factors for cancer in HIV patients in the Asia and Pacific region between 2000 and 2007.[Box 32.2] Of the 215 cancer patients evaluated, a higher proportion (71%) were male, with a mean age of 39 years for ADCs and 45 years for NADCs. Two-thirds (66%) of the HIV associated cancers were ADCs. The most common NADCs were lung, breast, hepatocellular carcinoma (HCC) and Hodgkin’s lymphoma. Patients with CD4 counts above 200/μL were roughly 80% less likely to be diagnosed with an ADC. Lower CD4 cell count and higher CDC stage were the only independent predictors of infection-related NADCs.
Box 32.2. Incidence of common cancers in HIV patients in the Asia and Pacific region from 2000 to 2007, a retrospective analysis of the TREAT Asia HIV Observational Database. (adapted from )
|CANCER||% cases (n=215)|
|High grade B-cell lymphoma|
|Primary CNS lymphoma (PCNSL)||3.7|
|Kaposi’s sarcoma (KS)||15.8|
|Non-small cell lung cancer (NSCLC)||5.6|
|Hepatocellular carcinoma (HCC)||2.3|
|Cancer of the penis||1.0|
|Cancer of larynx||0.5|
|Acute myeloid leukaemia||0.9|
|All non-AIDS defining||34.4|
Cancer patients with HIV generally do less well compared with HIV-negative subjects despite matched demographics. They usually present at a younger age and with advanced cancer stages. Due to HIV-related immunosuppression, their disease often runs an aggressive course. They tend to be less tolerant to both chemotherapy and radiotherapy and are more susceptible to treatment-associated toxicities, especially infections. Frequent interactions between HAART and other drug therapies pose major challenges to their cancer treatment. A multidisciplinary team approach should be adopted, drawing the collaborative expertise of HIV physicians, oncologists, haematologists, palliative care physicians, specialty nurses, pharmacists, clinical psychologists and social workers. HAART should be initiated as soon as possible with an aim to achieve optimal viral suppression during cancer therapy. This chapter discusses the management of selected cancers with special regards to HIV patients. Kaposi’s sarcoma (KS) and HIV-associated lymphoma are covered in Chapter E30 and Chapter E31 respectively.
Cervical cancer and cervical intraepithelial neoplasia
Invasive cervical cancer has been designated as an AIDS-defining illness by the Centers for Disease Control and Prevention (CDC) in 1993. In Hong Kong, cervical cancer is the 7th most common cancer in women with 500 new cases in 2015, accounting for 3.3% of all new cancers. It was the 9th major cause of female cancer deaths in 2016. The risk of cervical cancer is approximately 3-5 folds higher in women living with HIV. The pre-malignant lesion cervical intraepithelial neoplasia (CIN) is more common and more likely to recur in women with HIV infection, especially in the severely immunocompromised with CD4 count <200/μL. However, the prevalence of invasive cancer does not seem to correlate with the CD4 count. In some studies, immune reconstitution as a result of treatment with HAART causes a reduction in rates of CIN, but not cancer of cervix.
Extensive epidemiological data support the strong causal relationship between HPV infection and both invasive cervical cancer and CIN. More than 100 types of HPV have been identified. Around 40 of these can infect the anogenital tract, of which the oncogenic serotypes 16 and 18 account for 70% of cervical cancer, 80% of anal cancers, 60% of vaginal cancers and 40% of vulvar cancers. Among the sexually active, HIV-infected women have a substantially higher rate of persistent HPV infections of the types most strongly associated with cervical neoplasia. HPV coinfection with HIV is associated with higher grade squamous intraepithelial lesion and invasive cancer. Other predisposing risk factors include smoking, early coitus, high parity, multiple sexual partners, long term use of oral contraceptives (>5 years) and co-infection with other sexually transmitted infection agents such as herpes simplex virus 2 (HSV-2), Chlamydia trachomatis and Neisseria gonorrhoeae.
Primary prevention. Prevention of HPV infection and cofactors known to increase the risk of invasive cancer is the key to cervical cancer control. Cervical cancers are around twice as common in women who smoke. Promoting awareness and education to reduce high-risk behaviours are crucial, alongside discouraging tobacco use. There are currently three licensed vaccines (2-, 4- and 9-valent), offering protection against certain types of HPV, all of which are protective against types 16 and 18, the most common culprits of genital cancers. Clinical trials have demonstrated that these vaccines can prevent over 96% of CIN 2 or 3 caused by included HPV subtypes. Prophylactic HPV vaccination is recommended for girls between age 9 to 12; catch-up vaccination recommended for girls aged 13 to 26 years if they have not been vaccinated before. Vaccination does not eliminate the need for regular cervical screening. In Hong Kong, vaccination of girls in the appropriate age group is strongly recommended while HPV vaccination programme would soon be introduced in the public service. Some studies showed that HPV vaccine was safe and immunogenic when administered in HIV-infected individuals. Thus HPV vaccination should be recommended to all HIV-positive females age 9 through 26, similar to that for the general population.
Screening. The majority of cervical cancer deaths are potentially preventable by identifying premalignant lesions through systematic periodic screening. Cervical cytology by Pap smear remains the main tool for screening cervical cancer in Hong Kong. All newly diagnosed HIV-positive women should have their sexual and gynaecological history taken. In those who have initiated sexual activity, cervical cytology by Pap smear and pelvic examination should be performed as part of their initial medical assessment regardless of age. All abnormal Pap smears, including mild dyskaryosis or atypical squamous cells of undetermined significance (ASC-US) should be referred to specialist colposcopy services for biopsy to rule out CIN and cervical cancer.[Box 32.3] The American College of Obstetricians and Gynaecologists recommended that if the initial cytology screening result is normal, the next cytology screening should be in 12 months. Some experts recommended Pap test screening twice (every 6 months) in the first year of HIV diagnosis, and if both tests are normal, annual screening can be continued thereafter. If the results of 3 consecutive Pap tests are normal, some experts recommended follow-up Pap tests every 3 years thereafter.[Algorithm 32] Patients with CD4 count <200/μL and co-infection with HPV have higher rates of abnormal Pap smears. More frequent Pap smears may therefore be considered in these selected cases, although there is no recommended CD4 threshold below which more frequent cervical cytological sampling is indicated. PLWHA diagnosed with CIN or invasive cervical cancer should also be evaluated for field effect of HPV oncogenesis, including anal cancer or vulvar cancer.
Newer methods have been developed for cervical cancer screening, namely molecular HPV screening tests and visual inspection with acetic acid (VIA). Molecular HPV testing methods are based on DNA detection from high-risk HPV types in vaginal and/or cervical samples. This method is highly sensitive in detecting pre-cancerous lesions, however its specificity is relatively low compared with cytology. HPV testing in women younger than 30 years old is generally not recommended, because HPV infections in this age group are highly prevalent and often transient, leading to a high false positive rate. In cervical cancer primary screening, HPV testing can be used as a stand-alone test or co-testing with cytology for better sensitivity. Currently, there is paucity of long-term follow-up data on safety and efficacy of using HPV test as a stand-alone test for primary cervical cancer screening. It may be considered as a co-test with cytology in high-resource settings. VIA testing involves a trained provider examining the cervix after applying acetic acid to visualise cell changes on the cervix. This method is relatively simple and inexpensive, however its subjective endpoint makes this test very operator-dependent causing high variability in result accuracy. None of these tests have been validated for use in the HIV population.
Box 32.3. Cytological and histological classification for screening and diagnosis of cervical pre-cancer
|Cytological classification for screening||Histological classification for diagnosis|
|Pap smear result||Bethesda System||CIN||WHO descriptive classifications|
|Class III||LSIL||CIN 1 including flat condyloma||Koilocytosis|
|Class III||HSIL||CIN 2||Moderate dysplasia|
|Class III||HSIL||CIN 3||Severe dysplasia|
|Class IV||HSIL||CIN 3||Carcinoma in situ|
|Class V||Invasive carcinoma||Invasive carcinoma||Invasive carcinoma|
|CIN: cervical intraepithelial neoplasia; LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion; ASC-US: atypical squamous cells of undetermined significance; ASC-H: atypical squamous cells, cannot exclude a high-grade squamous epithelial lesion.|
Management of cervical intraepithelial neoplasia (CIN). The management of abnormal smears and CIN in HIV-positive women does not differ from that in the general population. Although both surgical failure and disease recurrence rates are higher in HIV patients, recommendation to treat only lesions that are CIN 2 or higher applies similarly to HIV and non-HIV cases. Risk factors for treatment failure in this population include CD4 cell count <200/μL, higher HIV viral load, compromised margins on the excisional specimen and not on treatment with HAART. If low-grade squamous intraepithelial lesion (LSIL) or CIN 1 is detected, close follow up with 6-monthly Pap smears is recommended, with repeat colposcopy annually, if Pap smear findings are similar. With high-grade squamous intraepithelial lesion (HSIL) or CIN 2 or 3, treatment should be offered. Treatment of these lesions is generally safe and effective. Laser conisation, large loop excision of the transformation zone (LLETZ), laser ablation and cryotherapy are the possible options. Endocervical extension seems to be more common in women with HIV, therefore loop excision may be less effective with higher recurrence rates compared with the general population. Topical 5-fluorouracil (5-FU) has been shown to be an effective adjunct to surgical and ablative therapies for reducing CIN recurrence in HIV patients.
Management of invasive cervical cancer. Women with HIV and invasive cervical cancer should be managed no differently from HIV-negative women. Treatment depends on disease staging according to the International Federation of Gynaecology and Obstetrics (FIGO) classification. For localised stage IA disease, cone biopsy with negative margins using cold knife conisation or loop electrosurgical excision procedure (LEEP), or radical trachelectomy (removal of cervix, upper vagina and parametrium), together with pelvic node dissection are suitable treatment options. Modified radical hysterectomy can be offered if fertility is not an issue. For stage IB disease with small tumours, non-fertility sparing radical hysterectomy with pelvic and para-aortic lymph node dissection is usually recommended. However in selected patients who wish to preserve fertility, radical trachelectomy is a reasonable alternative. Adjuvant therapy may be offered depending on risk factors. Treatment of other stage IB and II to IVA (spread to adjacent organs only) disease, would involve either radical hysterectomy with or without lymph node dissection or definitive pelvic external beam radiotherapy, combined with brachytherapy and concurrent cisplatin-based chemotherapy. Patients with stage IVB distant metastatic disease are offered systemic chemotherapy if deemed physically fit. Palliative individualised radiation may be an option for palliating symptoms, and also in those with multiple comorbidities and/or advanced age whom may be unable to tolerate aggressive chemo-radiation. In HIV patients with invasive cervical cancer, recurrence is common following treatment. Post-treatment surveillance is therefore imperative.
Anal Cancer and Anal Intraepithelial Neoplasia
Worldwide, anal cancer is an uncommon malignancy, but its incidence is 40 times higher in PLWHA compared with the general population, of which HIV-positive men who have sex with men (MSM) bear the highest risk. Its incidence is rising and seems not to be affected by the introduction of HAART. They usually present at a much younger age. Similar to carcinoma of the cervix, invasive anal cancer has a strong association with HPV infections (types 16 and 18) and the pre-malignant lesion anal intraepithelial neoplasia (AIN). Other adverse risk factors include receptive anal sex, multiple sexual partners, history of cervical/vaginal/vulvar cancers, perianal herpes simplex, anal condyloma and cigarette smoking. CD4 count does not appear to correlate with increased anal cancer risk. Individuals with a CD4 count of <50/μL have however been shown to experience more aggressive and advanced disease, with over 30% presenting with advanced disease stage. Concurrent problems with warts and haemorrhoids often reduce patients’ awareness of the potential risk of cancer in the anus, attributing to delay in diagnosis. Diagnosis is by anoscopic incisional biopsy. AIN grading used is similar to that for CIN.
Screening and Prevention. There is no standard recommendation for routine screening in the HIV population. The HIV Medical Association of the Infectious Diseases Society of America makes a weak recommendation for cytological screening with anal smear in MSM, women with a history of receptive anal intercourse or abnormal cervical Pap test, and those with genital warts. Early anoscopy with cytological evaluation is an established practice in managing symptomatic patients. Current recommendations aim at improving education and increasing awareness of clinicians, lowering threshold for biopsy in symptomatic patients and encouraging regular review for patients with known AIN. HPV vaccines are now licensed for preventing AIN, anal cancer and genital warts caused by HPV types included in the vaccines. The US CDC has recommend young boys and men 9 through 21 years of age to be vaccinated against HPV. In high-risk males including MSM, and those who are transgender, HIV-infected or otherwise immune-compromised, vaccination should extend through age 26 years.
Treatment. There is no standard treatment for HIV-positive AIN. Options include laser or radiofrequency ablation, electrocautery with hyfrecation or argon plasma coagulation, and topical imiquimod (an immunomodulator) or trichloroacetic acid. Sphincter preservation without compromising local control remains the major challenge in the treatment of invasive anal cancer. Surgically, complete resection can be offered to patients with carcinoma-in-situ and early stage I disease affecting only perianal skin, anal margin or anal canal, not involving the anal sphincter. Radical chemoradiation using mitomycin C, 5-FU and external beam radiation is the preferred treatment for stage II and III disease. Concurrent chemoradiation is safe at conventional doses in HIV patients, with complete response rates in excess of 80%. Abdominoperineal resection with permanent colostomy is usually reserved for salvage of residual disease. Salvage chemotherapy with 5-FU and cisplatin combined with a radiation boost may potentially avoid permanent colostomy. Although AIN or invasive anal cancer has not been shown to regress with HAART, resultant immune reconstitution may prevent infections during treatment, especially in those with low CD4 counts. There has been significant improvement in overall survival (OS) from anal cancer diagnosis since the introduction of HAART, with 5-year OS improving from 38% in the pre-HAART era to 68%. Patients should therefore receive the optimal HAART regimen with opportunistic infection prophylaxis during treatment.
Non-small cell lung cancer
Lung cancer remains the commonest cancer in the world. It also leads the ranking of common cancer sites and major cancer deaths in Hong Kong. The risk of non-small cell lung carcinoma (NSCLC) is 2 to 5 times higher in HIV patients. NSCLC is increasingly diagnosed in PLWHA, demonstrating well the shift to NADC. The reason for the trend was thought not to be solely attributed to heavy smoking, as similar increase in incidence was not seen in small cell lung carcinoma. Similar to the general population, adenocarcinoma is the most common histological subtype for NSCLC. This cancer is usually seen in the moderately immunocompromised, whose median CD4 count is 150-250/μL at diagnosis. Compared to non-HIV infected, PLWHA with NSCLC usually present at a younger age, have worse performance status and are at advanced stage of disease. Prognosis is also poorer. HAART does not appear to have a positive impact on the survival outcome. Diagnostic delays are frequently encountered, challenged by a wide range of differential diagnoses for an HIV patient with a lung shadow on plain X-ray. This translates to a small number of patients being eligible for curative surgery (<10%). Overall, suboptimal cancer treatment due to intolerance, augmented susceptibility to traditional treatment-related toxicities and increased aggressiveness of cancer in a weakened immune system, all add to higher cancer-related morbidity and mortality.
Screening and prevention. Some international guidelines are now advocating screening of high-risk individuals in the general population with non-contrast low dose CT (LDCT). High-risk candidates refer to individuals with ≥30 pack-year history of smoking and smoking cessation <15 years between ages 55 to 74 years. Those with smoking history ≥20 pack-years together with additional risk factors, screening is advised to start at an earlier age of 50 years. There is no role for chest radiograph and sputum cytology as screening tools. Large-scale data informing the potential role of lung cancer screening in HIV patients are limited, so screening decisions should follow that of the general population. Currently in Hong Kong, balancing local considerations, efficacy and cost-effectiveness, the Cancer Expert Working Group on Cancer Prevention and Screening considered that there is insufficient evidence to recommend lung cancer screening by LDCT, and no specific recommendations are made for PLWHA. Emphasis should be placed on tobacco control and encouraging smoking cessation.
Treatment. Early stage disease should be offered curative surgery. There is no specific data addressing the use of adjuvant chemotherapy in HIV-positive NSCLC. Treatment and follow-up strategy should follow that established for HIV-negative lung cancer. Stage I disease could be closely monitored after surgery. Adjuvant chemotherapy should be offered to patients with stage II disease as tolerated. Locally advanced disease should be treated with chemoirradiation according to HIV-negative guidelines. However, such form of treatment has been documented to be associated with profound immunosuppression, so caution must be exercised. Metastatic disease is associated with a poor prognosis in general. However, response and tolerance to different palliative systemic therapies can be widely variable depending on whether the tumours harbour any predictive or prognostic driver mutations. Survival rates in HIV-infected advanced NSCLC patients has improved since the widespread use of HAART, now comparable to matched HIV-negative patients.
Oncogene-driven therapy. In the era of personalised cancer therapy, tumour molecular analysis has become the standard of care in selecting favourable treatment options for certain target populations. International guidelines are universally recommending specific targeted therapies for oncogene-addicted tumours. Epidermal growth factor receptor (EGFR) mutations are the most common mutations in NSCLC/adenocarcinomas, with frequency ranging from 12-47% depending on patient ethnicity. EGFR mutation frequency is highest amongst South-East Asians, females and never smokers. EGFR tyrosine kinase inhibitors (TKIs), namely gefinitib, erlotinib, afatinib and osimertinib, have become the suggested first-line treatment for sensitising EGFR-mutation positive tumours. Prevalence of EGFR mutations in HIV-infected persons appears to be comparable to the general population. Outcomes in terms of response, duration of response and overall survival do not seem to be affected by HIV status in small studies. Therefore, EGFR mutation testing should be considered similarly in HIV-positive patients diagnosed with advanced NSCLC/adenocarcinoma. These TKIs in oral preparation are generally well tolerated. Use of EGFR TKIs require caution due to potential interaction with HAART causing more side effects. Other less frequent targetable driver mutations with commercially available targeted therapies include anaplastic lymphoma kinase (ALK), ROS1, MET, BRAF V600E mutations. Studies on TKI efficacy and tolerance in patients carrying rarer mutations in the HIV population are lacking. Patients should be managed similarly to HIV-uninfected patients. There is no specific data on monoclonal antibody targeted therapy or other multi-targeted therapies for HIV-positive metastatic NSCLC. The use of such agents should follow HIV-negative guidelines.
Systemic chemotherapy. For mutation negative or unknown tumours, palliative chemotherapy is one of the options for patients with good performance status. Earlier studies on HIV patients have included treatment regimens comprising mitomycin, vincristine/cisplatin and gemcitabine/carboplatin as single agent or as doublets, which were poorly tolerated with low response rates. CD4 counts prior to treatment did not seem to affect prognosis. Survival non-inferiority of pemetrexed/cisplatin to gemcitabine/cisplatin has been established in the HIV-negative population. Pemetrexed has a better toxicity profile and better rate of response when used in combination with cisplatin or carboplatin. Trials are now underway in investigating the efficacy and safety of pemetrexed-based chemotherapy in the setting of HIV. There is paucity of studies looking into second or subsequent lines of chemotherapy in this specific group of patients. Currently, management of progressive/ refractory disease generally follows that of HIV-negative population.
Immunotherapy. Since the advent of immune checkpoint inhibitors, survival of NSCLC patients without targetable driver mutations has much improved. Among these, programmed death receptor 1 (PD-1) pathway inhibitors (pembrolizumab and nivolumab) have been most investigated in lung cancer. Its benefit in the first and subsequent lines of therapy for advanced lung cancer in HIV-negative patients is well established, especially in tumours with higher programmed death ligand-1 (PD-L1) tumour proportion scores (TPS). Both agents are generally well tolerated. The efficacy of pembrolizumab in combination with conventional chemotherapy has recently been demonstrated in the first line setting regardless of PD-L1 expression, without addition of significant toxicities. Unfortunately, HIV patients have been excluded from immunotherapy clinical trials, so little is known about the safety and activity of these agents in PLWHA. A recently published study reported 7 HIV patients diagnosed with metastatic NSCLC treated with PD-1 inhibitors. All patients received HAART while on treatment. Partial responses were seen in 3 out of 7 cases and responses appeared to correlate with a PD-L1 TPS ≥50%. Treatment was well tolerated, with none experiencing grade 3 or 4 immune-related adverse events or immune reconstitution inflammatory syndrome (IRIS). None required dose interruption or discontinuation due to toxicity. Larger studies are warranted to determine the overall safety and efficacy of immune checkpoint inhibitors among lung cancer patients with HIV. Current indication for use should also follow that of HIV-negative patients.
Hepatocellular carcinoma (HCC) in HIV almost invariably occurs in the context of hepatitis B (HBV) and/or C (HCV) co-infection.[Chapter D28] These three viruses share similar modes of transmission and epidemiological profiles, and they closely interrelate in the pathogenesis of HCC. The incidence of HCC is rising in HIV patients. Whether this is a true epiphenomenon of the HAART era or only a confounding consequence of chronic viral hepatitis infection is debatable. HIV-infected HCC patients are usually younger at diagnosis and they tend to present with more advanced infiltrating cancers. They are often moderately immune-suppressed. Patients offered interventional therapies have outcome similar to that of the HIV-negative population. Some studies showed that fewer HIV-positive HCC patients were offered active curative treatment due to multiple co-morbidities, which translated into their poorer survival.
Screening. The British HIV Association (BHIVA) has recommended regular HCC surveillance in HIV/HBV/HCV co-infected individuals with or without cirrhosis at 6-month intervals with abdominal ultrasonography and serum alpha-fetal protein (AFP). More frequent surveillance in selected high-risk groups (for example those with persistently high HBV DNA titres) would require further justifications.
Prevention. HBV and HCV viral suppression can potentially reduce the risk of HCC. HBV vaccination is highly recommended in non-HBV infected HIV patients. Treatment of HCV and HBV infection in HIV/AIDS is covered in Chapter D28.
Treatment. Multidisciplinary management approach similar to that for HIV-negative patients should be adopted. Assessment of the degree of cirrhosis by Child-Pugh classification should be incorporated into the decision-making for HCC treatment. The BCLC staging system classifies the tumour into early, intermediate, advanced and terminal stages.
Early stage disease should be offered curative treatment wherever possible. Prognosis is good and comparable to HIV-negative subjects with 5-year overall survival up to 70%. The choice of treatment with surgical resection, liver transplantation, radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) would largely depend on the candidate’s liver reserve, functional status and tumour characteristics. Liver transplantation should be offered to HIV-infected patients by applying the Milan criteria (three lesions less than or equal to 3cm or single lesion less than 5cm in diameter). Liver transplantation may even have superior results compared to resection alone in HIV-positive HCC patients using the UCSF criteria (three lesions less than or equal to 4.5cm or single lesion less than 6.5cm and cumulative tumour size less than 8cm). Bridge therapies before transplantation should be considered as in HIV-negative counterparts.
Locoregional therapy with transcatheter arterial chemoemobolisation (TACE) is the treatment of choice for intermediate stage disease.
HCC is a very chemo-resistant tumour. Studies from past decades with the use of different chemotherapy or immunomodulatory agents in advanced HCC have failed to show much survival benefit. However, a lot of advances have been made in recent years in improving the dismal prognosis in this group of patients. The oral multikinase inhibitor sorafenib and oral vascular endothelial growth factor receptor (VFGFR) inhibitor lenvatinib are now available with significant response rate and survival benefit, for patients with good liver reserve and unresectable tumours not suitable for locoregional therapies or advanced/metastatic disease. Other multikinase inhibitors and VEGFR inhibitors including regorafenib, cabozantinib and ramucirumab can be used in subsequent lines of therapy upon disease progression. Immune checkpoint inhibitors are also recently approved for HCC treatment in patients previously treated with sorafenib. A multicenter study looking at the side effects of pembrolizumab in treating HIV patients with malignant neoplasms, including HCC, is now under accrual. External beam radiation has a limited role in HCC but can be an option in palliating symptoms.
Other neoplasms in HIV Patients
The relatively rare lymphoproliferative disorder Castleman’s disease in its multicentric form (MCD), is most commonly diagnosed in PLWHA. Patients often present with constitutional symptoms (eg. fever, night sweats, weight loss), multiple lymphadenopathy, hepatosplenomegaly, polyneuropathies, oedema, ascites, pleural/pericardial effusions, cytopaenias and multi-organ failure, hence potentially fatal. It is associated with HHV8, KS, POEMS syndrome and increased risk of NHL. Risk of MCD was shown to be related to a nadir CD4 count >200/μL, older age, no previous HAART and a non-Caucasian background. The diagnosis of MCD can only be established definitively by lymph node biopsy, supported by tissue HHV8 positivity and high expression of lambda light-chain restricted immunoglobulin M (IgM). Testing for HHV8 DNA in plasma by real-time polymerase chain reaction (PCR) may be a sensitive and specific tumour marker in HIV-associated MCD. It may help in making the diagnosis as well as monitoring of response to treatment and relapses. This test is however not widely available and currently not accessible in our locality. There is no gold standard treatment for MCD. Available options include single agent (vinblastine or etoposide) or combination (CHOP) chemotherapy, Rituximab (anti-CD20 monoclonal antibody), interferon-alpha, antiviral agents targeting HHV-8 and splenectomy. Anti-IL6 therapies have shown promising activity in HIV-negative patients with MCD. HAART did not seem to impact outcome of HIV-related MCD, but efforts should be made to maintain good HIV control throughout and after treatment to minimise complications and prevent relapse.
HIV infection also seems to confer additional risk of developing testicular seminomas, but there is no evidence to suggest any change in its incidence after widespread use of HAART. Other cancers are less well-described in PLWHA. There are anecdotal data suggesting that head and neck cancers, colon cancers and breast cancers may be more aggressive in HIV infection. Management of these cancers should be the same as that offered to HIV-negative patients. Recruitment into clinical trials should be encouraged to optimise management of these patients if available.
HAART and opportunistic infection prophylaxis in the face of malignancies
In patients who develop malignancies, HAART should always be optimised to ensure full viral suppression. The choice of HAART regimen should take into consideration common drug-drug interactions (DDI) with cytotoxic chemotherapy. Protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) may interact with chemotherapy agents metabolised by the cytochrome P450 system. Profound and prolonged neutropaenia has been observed when ritonavir-boosted PIs are used with therapy for NHL. Zidovudine (ZDV) is well known for its increased risk of myelosuppression. Some antivirals are best avoided in patients receiving chemotherapy with overlapping organ-specific toxicities, eg. tenofovir (nephrotoxic chemotherapy) and nevirapine (hepatotoxic chemotherapy).
Taxanes (paclitaxel and docetaxel), vinca alkaloids (vinorelbine), etoposide and TKI targeted therapies are all substrates or inhibitors of the cytochrome P450 system. Their use in combination with other drugs metabolised by this system may either decrease chemotherapy efficacy or potentiate risk of harmful toxicities. Ritonavir-boosted PIs are potent inhibitors of cytochrome P450 enzymes leading to increase in drug levels and toxicities. In contrary, NNRTIs are inducers of cytochrome P450 enzymes, thus potentially reduce drug exposure and compromising efficacy. They are therefore best avoided when the above drugs are used in the treatment of lung cancer. The newer class of integrase strand transfer inhibitors (INSTIs) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is thus the preferred choice of HAART. Among all the INSTIs, raltegravir is preferred as it has no effect on CYP450 or UGT-1A. Dolutegravir is metabolised mainly by UGT-1A with a minor contribution by CYP3A4, so the potential risk of DDI is small. However, elvitegravir, which requires boosting by the CYP450 inhibitor cobicistat, should be avoided during chemotherapy.
Studies have shown an increased risk of infectious complications in neutropaenic HIV patients. Prophylactic granulocyte colony-stimulating factor (G-CSF) can be considered in patients with low neutrophil nadir, prolonged neutropaenia or in the presence of central venous catheters. Concurrent use of myelosuppressive drugs should be avoided. The benefit of antibiotic prophylaxis for chemotherapy-induced neutropaenia is controversial, especially in low risk patients due to concern of selecting antibiotic resistance and antibiotic-related adverse events. Guidelines only recommend the consideration of prophylactic fluoroquinolone in patients undergoing high-risk chemotherapy at risk of prolonged and profound neutropaenia. There should be a low threshold for treatment of neutropaenic sepsis. The use of azole prophylaxis should be considered in preventing fungal infections in all patients during chemotherapy and radiotherapy. Pneumocystis jirovecii pneumonia (PCP) and Mycobacterium avium complex (MAC) prophylaxis should follow recommended guidelines according to CD4 counts. In addition, PCP prophylaxis should be given in all patients receiving both chemotherapy and/or radiotherapy irrespective of their CD4 levels. Herpes simplex virus (HSV) and varicella-zoster virus (VZV) seropositivity is common in PLWHA. HSV/VZV prophylaxis is recommended in HIV-associated cancer patients on treatment with a history of infection, to reduce the incidence and severity of reactivation. Primary prophylaxis against cytomegalovirus (CMV) is generally not recommended. Annual influenza vaccination is advocated, usually given at least 2 weeks before the start of chemotherapy or at least 1 week after the last cycle. People with HIV-associated malignancies should also be vaccinated against pneumococcus and hepatitis B virus.
Algorithm 32. Cervical screening in HIV patients
- Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, Biggar RJ; HIV/AIDS Cancer Match Study. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS 2006;20(12):1645-1654. link
- Petoumenos K, Hui E, Kumarasamy N, Kerr SJ, Choi JY, Chen YM, Merati T, Zhang F, Lim PL, Sungkanuparph S, Pujari S, Ponnampalavanar S, Ditangco R, Lee CK, Grulich A, Law MG; TREAT Asia HIV Observational Database. Cancer in the TREAT Asia HIV Observational Database (TAHOD): A retrospective analysis of risk factors. J Int AIDS Soc 2010;13:51. link
- World Health Organization. Comprehensive Cervical Cancer Control: A Guide to Essential Practice (2nd edition). Geneva: WHO, 2014. Available from: link
- Hong Kong College of Obstetricians and Gynaecologists. Guidelines for Cervical Cancer Prevention and Screening, 4th version, revised in November 2016. Hong Kong: HKCOG, 2016. Available from: link
- American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins − Gynecology. Practice Bulletin No. 167: Gynecologic Care for Women and Adolescents With Human Immunodeficiency Virus. Obstet Gynecol 2016;128(4):e89-e110. link
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (updated November 2018). Available at link
- Bower M, Palfreeman A, Alfa-Wali M, Bunker C, Burns F, Churchill D, Collins S, Cwynarski K, Edwards S, Fields P, Fife K, Gallop-Evans E, Kassam S, Kulasegaram R, Lacey C, Marcus R, Montoto S, Nelson M, Newsom-Davis T, Orkin C, Shaw K, Tenant-Flowers M, Webb A, Westwell S, Williams M; British HIV Association. British HIV Association Guidelines for HIV-associated Malignancies 2014. HIV Med 2014;15 (Suppl.2):1-92. link
- Reid E, Suneja G, Ambinder RF, Ard K, Baiocchi R, Barta SK, Carchman E, Cohen A, Gupta N, Johung KL, Klopp A, LaCasce AS, Lin C, Makarova-Rusher OV, Mehta A, Menon MP, Morgan D, Nathwani N, Noy A, Palella F, Ratner L, Rizza S, Rudek MA, Taylor J, Tomlinson B, Wang CJ, Dwyer MA, Freedman-Cass DA. Cancer in People Living with HIV Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018;16(8):986-1017. link
- Ostios-Garcia L, Faig J, Leonardi GC, Adeni AE, Subegdjo SJ, Lydon CA, Rangachari D, Huberman MS, Segahgal K, Shea M, VanderLaan PA, Cheng MP, Marty FM, Hammond SP, Costa DB, Awad MM. Safety and efficacy of PD-1 Inhibitors among HIV-positive patients with Non-small Cell Lung Cancer. J Thorac Oncol 2018;13(7):1037-1042. link
- Wilkins E, Mark N, Agarwal K, Awoyemi D, Barnes E, Bhagani S, Brook G, Brown A, Castelino S, Cook G, Fisher M, Geretti AM, James R, Kulasegaram R, Leen C, Mutimer D, Orkin C, Page E, Palfreeman A, Papineni P, Roger A, Tong CY; British HIV Association. British HIV Association guidelines for the management of hepatitis viruses in adults infected with HIV 2013. HIV Med 2013;14 (Suppl. 4):1-17. link
- European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC Clinical Guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908-943. link