CANCER PREVENTION INSTITUTE OF CANADA

Last updated: 15-Jan-2007

Human Immunodeficiency Virus

The human immunodeficiency virus (HIV) infects cells of the immune system. One of the sequelae of HIV infection is the well-known acquired immune deficiency syndrome (AIDS). Although not the greatest direct or even indirect cause of human cancers, the medical and sociopolitical realities around HIV infection (as well as associated AIDS) means that it has been a major driver of advances in the area of sexually transmitted infections such as HPV and blood-borne diseases such as HCV (the latter also related to injecting drug use).

HIV transmission can occur when blood, semen and pre-seminal fluid, vaginal fluid, or breast milk from an infected person enters the body of an uninfected person. Access can be gained through a vein (e.g., through an injection), the lining of the anus or rectum, the lining of the vagina or cervix, the opening to the penis, the mouth, other mucous membranes (e.g., eyes or inside of the nose), or cuts and sores. Contact with saliva, tears, or sweat has never been shown to result in transmission of HIV. Health care workers could come into contact with the virus through fluids surrounding the brain, spinal chord, and joints, as well as amniotic fluid.

Although spreading in heterosexual populations, men who have sex with men still account for over 50% of HIV transmission in the US.[1] Drug users also play a significant role in HIV incidence. Although opioid users represent a small proportion of the population, the predominant means of delivery of such drugs is by injection; thus there is a disproportionate contribution of this risky behaviour to HIV transmission, accounting for perhaps 5 to 10% of HIV infections. More precisely the risk arises through sharing injection equipment, which promotes blood-to-blood contact. The most efficient transmission of HIV occurs in blood transfusions and vertically from mother to child in pregnancy and delivery. Transmission through sexual encounters and drug injecting is not particularly efficient, but multiple exposures increase the risk to the point where these routes of HIV infection end up dominating the landscape.

Associated Cancers

As has already been noted in this report, HIV co-infection alongside other carcinogens such as HPV increases the risk of the associated cancers (e.g., in the case of HPV, it is true for certain types of cervical cancer). This relationship is also true for nonviral carcinogens such as tobacco smoke. For example, one study showed that lung cancer occurred at twice the rate in HIV-infected women as in non-infected women.[2]

Cancer development in HIV infection is promoted through a combination of immunosuppression and activation of inflammation.[3] The cancers associated with HIV, rather than being directly caused by the virus, are “opportunistic,” more or less exploiting the biological environment produced by HIV infection and AIDS.[4] It is not clear exactly what impact the improved survival of immunosuppressed patients may have on future rates of cancers associated with HIV.[5] Some believe that the incidence of Kaposi sarcoma and AIDS-related lymphomas is certain to increase.[6]

The most common virally-associated cancers and / or those with the highest relative risk with HIV co-infection are noted in the following table:[7]

Preventive Interventions

Sexual behaviour is the major factor determining the incidence of HIV infection, and a major target for early primary prevention. In this regard, the trends are not encouraging. UK surveys showed, for example, that since 1990, people have, on average, a greater number of lifetime partners, lower age at first intercourse, and more partners who do not use a condom consistently (especially among male homosexuals).[8],[9] Motivated and informed by this reality, UK authorities recently developed a conceptual framework for comprehensively reviewing evidence related to early primary intervention strategies.[10] The framework, which is useful in other developed settings such as Canada, included these features:

• The priority at-risk (or risky) populations involved in the strategy should be men who have sex with men, commercial sex workers, certain immigrant (especially African-origin) communities, and people with HIV.

• Interventions need to focus on influencing behaviours, e.g., increasing use of condoms, reducing the number of different partners, and encouraging only people with the same HIV status to have sex.

• Interventions need to address the underlying factors that give rise to risky behaviours, e.g., lack of knowledge and skills, availability of resources, discrimination, and substance abuse.[11]

• Interventions can be delivered at different levels, from individual (counseling, helplines) to groups (sex education) to whole communities (campaigns, professional development of healthcare personnel). A special topic of interest is peer-based and other approaches to preventing the exposure of women to HIV.[12],[13],[14]

• Behavioural change will probably require a large-scale program involving multiple components and levels.

The conclusion of the resulting UK literature review were sobering: there was very little or no evidence concerning the impact of interventions on any underlying factors or actual behaviours / health outcomes among any of the target populations. It is important to note that “no evidence” is not the same as evidence of ineffectiveness; it does, however, point to glaring research gaps. A Cochrane review from 2002, which looked at men who have sex with men, came up with a similar assessment: the evidence for behavioural interventions to reduce risky behaviours and HIV infection rates, though promising, is very limited; a meta-analysis of results suggested that the proportion of men engaging in unprotected sex was reduced by almost a quarter.[15] Another review from that year identified the following best practices for community-based programs dealing with sexually transmitted infections and HIV transmission:[16]

• establish community partnerships

• use opinion leaders and role models

• delivery by peer educators

• involvement of target groups in design of messages

• diffusion of interventions through existing social networks.

To this list, we can add two general points that emerged from the reviews noted earlier: multi-component interventions work best; and voluntary testing and counselling are more effective in combination with other interventions. The Cochrane review on the efficacy of counselling and testing is still in the protocol stage.

The most high profile method of HIV prevention is consistent and correct use of condoms. The efficacy of this approach has been proven, but the uptake is still low in many parts of the world. There are many interventions to promote condom use. The great majority of these have been behavioural interventions targeting individual-level barriers to employing condoms, and most have been conducted in a specific high-risk context (e.g., commercial sex work, drug use, homelessness, prisons).[17] While there have been acknowledged successes in these as well as population-wide settings, there have been no recent systematic reviews of intervention effectiveness, and no assessment of group or population approaches (even the Cochrane work is still at the protocol stage). The closest comprehensive Cochrane review to this topic noted that consistent use of condoms could reduce heterosexual HIV transmission by 80%.[18]

Structural approaches to promoting condom use may prove to be the most useful, though evidence remains to be gathered. The options include:[19]

• legislation of condom use among commercial sex workers

• improving the visibility, availability and accessibility of condoms

• free condom distribution

Since sharing syringes and needles is a very efficient way of spreading HIV, interventions related to reducing drug use or making it safer become important in controlling infection and associated diseases. While this topic has already been introduced earlier in the context of hepatitis C prevention, it is significant to note at this point that many studies of so-called structural interventions (e.g., syringe exchange programs) have demonstrated reductions in those behaviours that increase the risk of HIV transmission.[20] At least one recent systematic review has been published in the context of HIV per se. The Cochrane group looked at oral substitution treatment to reduce high-risk drug behaviours, concluding that there was clear, though limited, support for this approach as a means to reduce HIV infection.[21] Another study of almost 3,000 injection drug users suggested that targeting “incremental risk reduction” may be more successful than promoting abstinence.[22]

Some specialized populations and topics deserve mention. A Cochrane review of methods to prevent transmission of HIV from mother to child in pregnancy or delivery showed that two antiretroviral drugs were effective in risk reduction. One agent, nevirapine, was useful during labour itself; this drug is not indicated for long term monotherapy because of the potential for resistant viruses to emerge. A final method which reduced HIV transmission to the child was birth by elective caesarean section.[23] The related topic of breastfeeding is being examined by the Cochrane group, but their assessment is in process. The possible interventions to prevent HIV transmission include formula feeding, early weaning, treatment of breast milk and antiretroviral prophylaxis in child and / or mother.[24]

Employees in healthcare have a definite risk for inadvertent exposure to HIV. Procedures and protocols like those recommended by the World Health Organization[25] need to be in place to minimize the danger.

Heterosexual transmission of HIV is increasing globally. This reality prompted a 2002 review of interventions directed to heterosexual men. Elwy et al. found 8 studies designed to reduce sexually transmitted infection (including HIV) rates.[26] There were 5 successful programs, which included on-site individual counselling and HIV testing, mass communications regarding risk reduction and motivation and skills education. Another 2002 review confirmed that interventions can have a positive effect on risky behaviours and HIV rates.[27] Most of the included studies took place in healthcare settings, and included the following features: information on HIV and risk behaviours, along with technical and personal skills.

According to the Centers for Disease Control, people under 25 account for 50% of new HIV infections in the US. This has created a great deal of urgency around creating effective prevention programs. A 2003 review of sexual risk reduction among youth found positive results in just over half of the 23 studies identified.[28]

Of course, many of the early primary prevention methods related to HIV are based on the knowledge that an infection is in place, and then limiting the spread of that infection. Thus, interventions aimed at promoting voluntary testing is theoretically very important. While the Cochrane work on this area is just starting, an earlier review suggested that testing still remains to be proven as useful in early primary prevention; on the other hand, its role in preventing disease development among the already infected has been demonstrated.[29]

There is evidence that the “cocktail” of antiretroviral drugs taken by HIV-positive patients can be preventive against cancer development. The incidence of Kaposi sarcoma and AIDS-related lymphoma have dropped as the drugs have come into routine use.[30] Secondary prevention also comes into play, in the sense that antiretroviral therapy seems to actually resolve established Kaposi sarcoma lesions. Information on treatments targeted to specific HIV-influenced cancers is provided in the sections of this report dealing with the relevant etiologic factor. The sort of immunity-boosting therapies being considered for some of these cancers may in turn be used to treat HIV infection.[31]

Primary prevention after voluntary exposure to HIV (e.g., through sexual intercourse, intravenous drug needle sharing), which usually means the use of antiretroviral drugs in a prophylactic way, is a controversial topic. It is an expensive proposition, and there are no controlled trials supporting its efficacy. Nevertheless, the demand for such an intervention is great, prompting a Cochrane review of the limited evidence available; so far, only the protocol has been published.[32] A specialized application for prophylactic treatment is in healthcare workers who experience a needle-stick or some other accidental form of exposure; again, the investigation of this type of intervention has only just begun at the Cochrane group.

HIV vaccine development remains an intense area of focus. Since 1987, more than 30 candidate vaccines have been tested in approximately 60 Phase I/II trails, involving more than 10,000 healthy volunteers. Most of these trials have been conducted in the US and Europe, but several have also been conducted in developing countries. The results have confirmed the safety of the vaccines. Currently, there are only two candidate vaccines being evaluated in Phase III trials.[33]

[2] Phelps RM, Smith DK, Heilig CM et al. Cancer incidence in women with or at risk for HIV. International Journal of Cancer. 2001; 94(5): 753-7.

[3] Boshoff C, Weiss R. AIDS-related malignancies. Nature Reviews Cancer. 2002; 2(5): 373-82.

[4] Scadden DT. AIDS-related malignancies. Annual Reviews of Medicine. 2003; 54: 285-303.

[5] Beral V, Newton R. Overview of the epidemiology of immunodeficiency-associated cancers. Journal of the National Cancer Institute Monograph. 1998; (23): 1-6.

[6] Marco M. Acquired immunodeficiency syndrome-related cancers: the community perspective. Journal of the National Cancer Institute Monograph. 1998; (23): 21-2.

[7] Boshoff C, Weiss R. AIDS-related malignancies. Nature Reviews Cancer. 2002; 2(5): 373-82.

[8] Johnson AM, Fenton KA, Mercer C. Phase specific strategies for the prevention, control, and elimination of sexually transmitted diseases: background country profile, England and Wales. Sexually Transmitted Infections. 2002; 78 Suppl 1: i125-32.

[9] Hickson F, Nutland W, Doyle T et al. Making it Count: a Collaborative Planning Framework ot Reduce the Incidence of HIV Infection During Sex Between Men. London: Sigma Research; 2000.

[10] Ellis S, Barnett-Page E, Morgan A et al. HIV Prevention: a review of reviews assessing the effectiveness of interventions to reduce the risk of sexual transmission. NHS Health Development Agency.2003. Available at http://194.83.94.67/uhtbin/hyperion_image.exe/EBBD_HIV_pdf_ft. Accessed June 2005.

[11] Semaan S, Des Jarlais D, Sogolow E et al. Interventions to modify sexual risk behaviors for preventing HIV infection in drug users. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews.1998.

[12] Tholandi M, Kennedy G, Wilkinson, D. Female condom for preventing heterosexually transmitted HIV infection in women. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews.2002.

[13] Doull M, O'Conner A, Robinson V et al. Peer-based interventions for reducing morbidity and mortality in HIV-infected women. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews.2004.

[14] Ehrhardt AA, Exner TM. Prevention of sexual risk behavior for HIV infection with women. Aids. 2000; 14 Suppl 2: S53-8.

[15] Johnson WD, Hedges LV, Diaz RM. Interventions to modify sexual risk behaviors for preventing HIV infection in men who have sex with men. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews. 2002.

[16] Ross MW, Williams ML. Effective targeted and community HIV/STD prevention programs. Journal of Sex Research. 2002; 39(1): 58-62.

[17] Myer L. Morroni C, Mathews, C et al. Structural and community-level interventions for increasing condom use to prevent HIV and other sexually transmitted infections. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews.2001.

[18] Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews.2005.

[19] Myer L. Morroni C, Mathews, C et al. Structural and community-level interventions for increasing condom use to prevent HIV and other sexually transmitted infections. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews.2001.

[20] Des Jarlais DC. Structural interventions to reduce HIV transmission among injecting drug users. Aids. 2000; 14 Suppl 1: S41-6.

[21] Gowing L, Farrell M, Bornemann R et al. Substitution treatment of injecting opioid users for prevention of HIV infection. Cochrane Drugs and Alcohol Group Cochrane Database of Systematic Reviews.2004.

[22] Celentano DD, Munoz A, Cohn S et al. Dynamics of behavioral risk factors for HIV/AIDS: a 6-year prospective study of injection drug users. Drug and Alcohol Dependence. 2001; 61(3): 315-22.

[23] Brocklehurst P. Interventions for reducing the risk of mother-to-child transmission of HIV infection. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews.2001.

[24] Tholandi M, Wilkinson D, Dabis F et al. Interventions to decrease the risk of mother-to-child transmission of HIV-1 through breast milk. Cochrane HIV/AIDS Group Cochrane Database of Systematic Reviews.2003.

[25] See http://www.avert.org/needlestick.htm. Accessed June 2005.

[26] Elwy AR, Hart GJ, Hawkes S et al. Effectiveness of interventions to prevent sexually transmitted infections and human immunodeficiency virus in heterosexual men: a systematic review. Archives of Internal Medicine. 2002; 162(16): 1818-30.

[27] Neumann MS, Johnson WD, Semaan S et al. Review and meta-analysis of HIV prevention intervention research for heterosexual adult populations in the United States. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 2002; 30 Suppl 1: S106-17.

[28] Pedlow CT, Carey MP. HIV sexual risk-reduction interventions for youth: a review and methodological critique of randomized controlled trials. Behavior Modification. 2003; 27(2): 135-90.

[29] Weinhardt LS, Carey MP, Johnson BT et al. Effects of HIV counseling and testing on sexual risk behavior: a meta-analytic review of published research, 1985-1997. American Journal of Public Health. 1999; 89(9): 1397-405.

[30] Boshoff C, Weiss R. AIDS-related malignancies. Nature Reviews Cancer. 2002; 2(5): 373-82.

[31] Kieff E. Current perspectives on the molecular pathogenesis of virus-induced cancers in human immunodeficiency virus infection and acquired immunodeficiency syndrome. Journal of Nationall Cancer Institute Monograph. 1998; (23): 7-14.

[32] Martin NV, Almeda J, Casabona J. Effectiveness and safety of HIV post-exposure prophylaxis after sexual, injecting-drug-use or other non-occupational exposure. Cochrane HIV/AIDS Group. Cochrane Database of Systematic Reviews. 2005.

[33] See the World Health Organization website at http://www.who.int/hiv/topics/vaccines/Vaccines/en/. Accessed June 2005.