HIV-associated malignancies in the HAART era: flickers of hope and understanding
Mark Bower PhD, FRCP, for HIVandHepatitis.com
The oncological themes of the World AIDS conference focused on the ways in which HAART has affected AIDS-related malignancies and their management including pre-invasive lesions of the cervix and anus.
There was little discussion in Barcelona of the management of Kaposi’s sarcoma and not a single abstract on primary cerebral lymphomas, reflecting the falling incidence of these tumours where there is access to HAART. It should, however, be recalled that Kaposi’s sarcoma remains the most common cancer in sub-Saharan Africa and its optimal management in a resource-poor setting has yet to be adequately defined.
The changing incidence of cancers since the introduction of HAART
It has been well established from individual cohort studies as well as meta-analyses that the incidence of the two most common AIDS-related malignancies, Kaposi’s sarcoma and non-Hodgkin’s lymphoma, have decreased since the era of HAART and a number of similar studies that reconfirmed this data were presented. [1, 2 and 3]
Some of these studies also addressed the incidence of solid tumours and have found increasing rates of these tumours since the beginning of the HAART era. For example bladder (Relative Risk =1.58, CI=1.04-2.41) and prostate (RR=1.63, CI=1.32-1.99) cancers in the veterans’ study.  Similarly a UK cohort study found that seminoma,  and lung cancer  occurred at increased frequency in the post HAART era. Whilst the US women’s interagency HIV study also found an increased relative risk of lung cancer. 
However, data from US linked AIDS and cancer registries suggests that there is no clear relationship between the degree of immunosuppression as measured by CD4 cell count and the development of non-AIDS defining malignancies. . Moreover, the multicentre AIDS cohort study (MACS) suggests that there has been a fall in the incidence of non-AIDS defining malignancies in the era of HAART. 
Advances in lymphoma therapy
Although the concomitant use of HAART has been associated with an improved overall survival in systemic non-Hodgkin’s lymphoma  and now also Hodgkin’s disease , it is suggested that this improvement represents an advance in the control of the infectious complications of the immune deficiency rather than better control of the tumour and that there is little evidence for improved tumour response rates.
New approaches that aim to achieve better tumour control have recently focused on the over-expression of the MDR-1 P-glycoprotein efflux pump by AIDS related lymphomas. Intriguingly the protease inhibitors are also substrates for this efflux pump that reduces intracellular concentrations of cytotoxic chemotherapy agents within the lymphoma cells.
One widely adopted strategy is the use of continuous infusions of chemotherapy including the widely used CDE regimen developed by Dr Sparano. An alternative approach is the use of liposomal encapsulation of anthracyclines to prolong their half-life and thus circumvent the protection given by the MDR-1 pump. Thus, Dr Levine has used a CHOP based schedule with the doxorubicin substituted by a liposomal version (TLC D99, Myocet) and has achieved a remarkably high complete response rate of 79% in a phase I/II trial that enrolled 23 patients. 
More aggressive approaches have also been advocated in response to the improved outcome of HIV infection since the introduction of HAART. It is against this background that the French and Italian group describe the favourable outcomes using the Stamford V regimen with HAART in patients with HIV-associated Hodgkin’s disease.
They achieved a complete remission rate of 81% in 59 patients and 25% subsequently relapsed. The actuarial overall survival and disease free survival at two years are 68% and 70%, respectively.  These results, although not as good as for the immunocompetant population, are considerably improved on the historical data from the pre-HAART era.
Similarly the use of high dose chemotherapy and autologous peripheral stem cell rescue for refractory or relapsed lymphoma is an established technique that until recently was deemed too aggressive for patients with HIV infection but that has now been introduced as an additional successful therapy for selected patients. 
Rituximab antibody therapy has also been found to be a useful addition to the therapy of aggressive B-cell lymphomas that express CD20 in the general population and is finding a role in refractory or relapsed HIV–associated non-Hodgkin’s lymphomas despite the prolonged B-cell cytopenia that follows this therapy. 
HAART and Kaposi’s Sarcoma
The mechanism of the falling incidence of Kaposi’s sarcoma (KS) and the response of the tumour to HAART remains uncertain. A direct anti-angiogenic effect of the protease inhibitors is described by Dr Ensoli using a murine model  and it is hypothesised that this accounts for the regression of KS with HAART.
However, a large clinical cohort study which confirmed the fall in KS incidence found that non-nucleoside reverse transcriptase inhibitor (NNRTI) based HAART was at least as effective as a protease inhibitor (PI) based regimen at preventing KS. They also found that most KS now occurred in antiretroviral-naïve patients and that patients developing KS whilst on HAART are usually experiencing treatment failure. 
Instead, this action may operate via the reconstitution of natural killer cell activity against Human Herpesvirus 8 which was demonstrated in vitro in peripheral blood monocytes from patients whose KS lesions had regressed on HAART therapy, also by Dr Ensoli’s group. 
Finally, anecdotal reports have described Kaposi’s sarcoma in the context of immune reconstitution. A report from Canada included three patients who developed severe visceral KS following the start of protease inhibitor-based HAART. This was associated with a rapid decline of plasma HIV viral load but no significant rise in CD4 cell counts. 
These conflicting data have failed to resolve the mechanism of KS regression and prevention by HAART and there is evidence for both indirect immunological mechanisms controlling HHV8 and a direct anti-angiogenic action on KS lesions.
Cervical and anal lesions
It has been widely recognised that HAART reduces the incidence of both KS and NHL where viral oncogenesis coupled to immune deficiency have a recognised role in tumour pathogenesis. It was therefore thought that HAART might have a similar beneficial influence on both cervical and anal cancers and their precursor lesions.
Both tumours are associated with high risk genotypes of human papilloma virus (HPV) and are also found at higher frequency in other forms of immunosuppression. However the unfolding story in these epithelial tumours is less encouraging.
There appears to be no reduction in the development of human papilloma virus (HPV)-related cervical lesions in women who start on HAART with normal cytology at baseline and who are followed prospectively at six month intervals. There was no difference in the rate of development of lesions between women not treated with antiretrovirals, treated with reverse transcriptase inhibitors alone or with HAART, and all women had high rates of SIL (squamous intraepithelial lesions) (4-10%) at a mean follow-up of 40 months. 
In addition, HAART was a risk factor for cervical SIL in one study although this was not evaluated independently of the CD4 cell count.  Moreover there is no reduction in the HPV viral load in vaginal secretions in women following the start of HAART. 
The apparent lack of beneficial actions of HAART on pre-invasive anal lesions also increases the need to identify these lesions so that patients at risk of anal cancers can be monitored closely and treated at early stages. Although in this context the value of screening remains uncertain, the ability of anal cytological examination to pick up these lesions was confirmed in two abstracts. [22 and 23]
HIV-associated lung cancer
A large single institution cohort study of 8,636 HIV-positive patients (36,158 patient years of follow up) from the Chelsea & Westminster Hospital, London, has assessed the relative risk of lung cancer and compared it with the age and gender matched general population. They found that the relative risk was not increased during the pre-HAART era but the relative risk is 8 in the post-HAART era, suggesting a significant risk of lung cancer, a tumour not traditionally associated with immune suppression. 
This finding of a high relative risk of lung cancer during the HAART era is supported by an evaluation of mortality in HIV-positive patients at a US sub-urban hospital where 3/15 of the deaths were attributed to lung cancer. 
The poor prognosis described by Dr Powles is confirmed in a smaller study from California.  It remains to be seen how important non-AIDS defining tumours will become in the post-HAART era and how large a clinical burden they will represent.
The finding of an increasing incidence of these solid tumours, often developing after a prolonged period of HIV seropositivity and chronic immunosuppression, may also lead to a clearer understanding of the role of immune surveillance in common solid tumours such as lung cancer.
Dr Bower is Consultant Medical Oncologist, Chelsea and Westminster Hospital, London, UK.
All references are to the Programme and Abstracts of the XIV International AIDS Conference. July 7-12, 2002. Barcelona, Spain.
- MP Carrieri and others. Reduced incidence of Kaposi’s sarcoma and of systemic non-Hodgkin’s lymphoma in HIV-infected individuals treated with HAART. Abstract TuPeC4728.
- IE Salit and P Chantler. HIV-related Malignancies in the HAART era. Abstract ThPeB7310.
- KA McGinnis and others. Pre and post HAART cancer incidence among HIV positive veterans. Abstract TuPeC4740.
- T Powles and others. Multicentre cohort study of testicular cancer in men with HIV. Abstract ThPeB7313.
- T Powles and others. HIV related lung cancer in the pre and post HAART era. Abstract WePpB2094.
- N.A. Hessol and others. Increased incidence of cancer among participants in the women’s interagency HIV study. Abstract ThPeC7482.
- SM Mbulaiteye and others. Immune deficiency and risk for malignancy among persons with AIDS. Abstract ThPeC7478.
- EC Seaberg and others. The impact of highly active antiretroviral therapy (HAART) on cancer incidence in the Multicenter AIDS Cohort Study (MACS). Abstract ThPeC7484.
- AS Lascaux and others. Beneficial effect of highly active antiretroviral therapy (HAART) on the prognosis of AIDS-related lymphomas (ARL). Abstract ThPeC7479.
- JM Ribera and others. Favorable impact of HAART on response to therapy and survival in patients with AIDS-related Hodgkins’s disease (ARHD). Abstract ThPeB7315.
- AM Levine and others. Liposomal doxorubicin (TLC D99, Myocet) in combination with cyclophosphamide, vincristine and prednisone is an active regimen for HIV associated lymphoma. Abstract WePpB2091.
- M Spina and others. Stanford v regimen and highly active antiretroviral therapy (haart) in patients (pts) with HD and HIV infection (HD-HIV). Abstract ThPeB7311.
- S Casari and others. High Dose Therapy and Autologous Peripheral Blood Stem Cell (PBSC) Transplantation in Pts. with HIV-Associated Lymphoma Refractory to or Relapsed after First-Line Chemotherapy. Abstract ThPeB7317.
- LG Goelkel and others. HIV-related lymphoma: Rituximab concomitant to second-line chemotherapy following tumor progression under CHOP or early relapse. Abstract ThPeB7318.
- C Sgadari and others. HIV protease inhibitors block angiogenesis and promote regression of Kaposi’s sarcoma. Abstract WePeA5760.
- S Portsmouth and others. Falling incidence of AIDS related Kaposi’s sarcoma on HAART. The protective effect of NNRTIs. Abstract ThPeC7485.
- MC Sirianni and others. NK cell activity controls HHV-8 latent infection and is restored upon HAART in AIDS patients with regressing Kaposi’s sarcoma. Abstract TuPeA4428.
- DM Forrest and others. Severe visceral Kaposi’s sarcoma due to immune reconstitution associated with reduction in plasma viral load without increase in CD4+ count. Abstract ThPeB7187.
- F Lillo and others.  Incidence of HPV related cervical lesions in HIV positive/ Pap Test negative women undergoing different antiretroviral treatments. WePeB6047.
- R Kreitchmann. Risk factors for Cervical Squamous Intraepitelial Lesions in HIV-1 positive women in Porto Alegre – Brazil. Abstract ThPeB7316.
- LJ Conley and others. Does HAART have an effect on genital HPV DNA virus load in HIV-infected women? Abstract ThPeB7309.
- SM Fine and others. Anal PAP smears in HIV+ patients at a community based clinic. Abstract ThPeC7488.
- R Alfonzo and others. Anal cytology screening as a useful test for diagnosis of anal dysplasia in HIV positive patients. Abstract ThPeC7544.
- T Powles and others. HIV related lung cancer in the pre and post HAART era. Abstract WePpB2094.
- J Verley and others. Evaluation of mortality in HIV-infected patients at a suburban hospital. Abstract ThPeB7382.
- LA Cone and others. Histology and clinical behavior of lung cancer in patients with AIDS. Abstract B10272.
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