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Poppers and HHV-8 and Kaposi's Sarcoma

HHV-8 is the virus necessary for the development of  Kaposi's Sarcoma. However, everyone with HHV-8 does not develop Kaposi's Sarcoma.  There is a mystery about the disproportionate amount of gay men who are HHV-8 sero positive. There is also a mystery about why some gay men who have HHV-8 develop KS and others do not. HHV-8 is most commonly found in saliva. Does deep kissing transmit HHV-8? Does everyone exposed to  HHV-8 in saliva get infected?  Are gay men exposed to HHV-8 when they use saliva as an anal lubricant?

What cofactors increase the risk of HHV-8 infection in gay men?

What cofactors increase the risk of gay men with HHV-8 progressing to KS?

Is poppers use a cofactor for HHV-8 seropositivity and KS among gay men?

Colman,Rachel and Blackbourn,David J. "Risk factors in the development of Kaposi's Sarcoma." AIDS Volume 22(13), 20 August 2008, p. 1629-1632. "Besides increasing sex drive and potentially sexual behaviors associated with KSHV transmission, recreational amyl nitrite use may alter T-cell function, increasing vulnerability to infectious agents and perhaps expression of angiogenic VEGF, important in KS development."

"The strong dose dependent relation between popper use and HHV-8 infection has been found consistently in epidemiological studies. A number of explanations have been offered for this association, ranging from the effects of nitrates on immune function to the vasodilatory properties of these drugs. We found evidence for amyl nitrate use being significantly associated with sexual behaviors that could confer a greater risk of STI acquisition. Therefore the question of whether the relation between amyl nitrates and HHV-8 is biological or behavioural remains unanswered."  Corey Casper, Journal of Sexually Transmitted Infections 2006;82:229-235. 

Fung HL & Tran DC "Effects of inhalant nitrites on VEGF expression: A feasible link to Kaposi’s sarcoma?" Journal of Neuroimmune Pharmacology 2006 Sep 1 (3): 317-22. PMID 18040808  "In a series of studies, we showed that acute and chronic in vivo exposure to isobutyl nitrite (a representative inhalant nitrite) produced significant tissue-dependent alterations in the expression of a number of cancer- and angiogenesis-related genes in mice. In particular, hepatic mRNA and protein expression of vascular endothelial growth factor (VEGF) was significantly stimulated. The in vivo growth rate of a subcutaneous VEGF-responsive tumor was also shown to be accelerated by inhalant nitrite exposure. Because the development of KS is extensively linked to VEGF and its receptors, the purported link between inhalant nitrites and KS may be explained mechanistically, at least in part, through stimulation of VEGF expression by these inhalants."

Tran DC et al. "Effects of repeated in vivo inhalant nitrite exposure on genes expression in mouse liver and lungs." Nitric Oxide 2006 June; 14(4);279-289. "In conclusion, multiple exposures to inhalant nitrite appeared to cause alterations in the expression of a number of genes relating to cancer and angiogenesis," PMID 16288974

Mbulllaiteye Sam et al. "Risk factors for human herpes virus 8 seropositivity in the AIDS Cancer Cohort Study." Jounral of Clinical Virology 2006 April; 35(4):442-449. PMID 16414306

Casper C et al. "HIV serodiscordant sex-partners and the prevalence of HHV-8 infection among HIV negative men who have sex with men: baseline data from the EXPLORE study." Sexually Transmitted Infections 2006; 82(3): 229-235. PMID 16731675 "Popper (amyl nitrate) use was also significantly associated with HHV-8 infection. Compared with men who never used "poppers," use less than once a week was associated with a 1.3-fold increased odds of HHV-8 infection (95% CI 0.9 to 1.9, p =0.14), 1-2 times per week 2.9-fold increase (95% CI 1.6 to 5.4, p =<0.01), and >3 days per week 3.4-fold increase (95% CI1.4 to 8.6, p = 0.01). However, popper use was also significantly associated with the median number of sex partners, and performing rimming with >5 lifetime HIV unknown sex partners (p=<0.001)."

Chin-Hong PV et al. "Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study." Journal of National Cancer Institute 2005 June 15; 97(12): 896-905. PMID 15956651

Tran DC et al. "Inhalant nitrite exposure alters mouse hepatic angiogenic gene expression." Biochem Biophys Research Communications 2003 Oct 17; 310(2):439-45. "These results demonstrate that in vivo exposure to an inhalant nitrite results in altered tissue expression of vascular endothelial growth factor (VEGF) and its receptors, suggesting that some of its toxicological effects may be mediated partly through a mechanism involving angiogenesis." PMID 14521929

Casper C et al. "Correlates of prevalent and incident KS-associated herpesvirus infection in men who have sex with men." Journal of Infectious Diseases 2002 April 1; 185(7): 990-993. PMID 11920325 "Reporting > or = 1 HIV-positive partner (OR, 5.9; 95% CI, 1.8-19.3), amyl nitrite use (OR, 7.0; 95% CI, 2.1-23.0), and lymphadenopathy in the past 6 months (OR, 7.7; 95% CI, 1.9-31.0), correlated with KSHV seroconversion." "The relationship of amyl nitrite use to KSHV seroincidence was further investigated by adding the significant univariate variables to the model, one at a time. The OR did not change after adding either HSV-2 infection or bacterial STIs to the model, but it declined from 7.0 (95% CI, 2.0-24.9) to 5.5 (95% CI, 1.4-20.8)after adding a reported history of bathhouse use. Thus, these variables did not mitigate the association between amyl nitrite use and KSHV seroconversion."

Martin JN et al. "Evaluation of specific sexual practices as routes of HSHV transmission among homosexual men." Fourth International Workshop on KSHV and Related Agents 2001 Aug; Oral presentation and printed abstract. University of California, Santa Cruz. "Even with adjustment for sexual practices, inhaled nitrite use during sex was associated with KSHV infection.(OR=2.4,p >0.01)." Unpublished.

Pauk et al. "Mucosal shedding of human herpesvirus 8 in men." New England Journal of Medicine 2000 Nov 9; 343(19):1369-77. PMID 11070101 "Among 92 men who have sex with men who were seronegative for HIV, a history of sex with a partner who had Kaposi's sarcoma, deep kissing with an HIV-positive partner, and the use of amyl nitrite capsules ("poppers") or inhaled nitrites were independent risk factors for infection with HHV-8."

Martin, J et al. "Salivary Shedding of KSHV among homosexual men." Abstract at 3rd International KSHV Workshop at the University of Massachusetts at Amherst, July 6-10 2000. "In multivariate analysis among those KSHV-positive or with KS, KSHV-saliva positivity was associated with HIV infection (OR=2.2,p=0.027), and recreational use of "poppers"(OR=2.2,p=0.049)..." "If their roles are confirmed, the use of "poppers", long associated with KS per se,....may be escalating the KS epidemic in homosexual men by increasing the infectiousness and/or potentiating viral activity in infected men."

Soderberg LS "Increased tumor growth in mice exposed to inhaled isobutyl nitrite." Toxicology Letters 1999 Jan 11; 104(1-2):35-41. PMID 10048747 "To determine if exposure to nitrite inhalants could alter tumor growth, syngeneic PYB6 tumor cells were injected into groups of mice. Exposure of these mice to inhaled isobutyl nitrite increased both the tumor incidence and the tumor growth rate by almost 4-fold. Following only 5 daily exposures to the inhalant, the induction of specific T cell mediated cytotoxicity was inhibited by 36%. Similar inhalation exposures inhibited the tumoricidal activity of activated macrophages by 86%. The data suggest that exposure to abuser levels of a nitrite inhalant compromised tumor surveillance mechanisms."

James JS "Poppers: large cancer increase and immune suppression in animal tests." AIDS Treatment News 1999,317; PMID 11366993. " A study on mice injected with cancer cells and then exposed to isobutyl nitrite (poppers) revealed that inhalant-treated mice developed more readily and rapidly than control mice. The control mice were also injected with cancer cells, but only breathed air. Related studies found that poppers suppress certain immune functions involved in killing tumor cells."

Soderberg LS "Immunomodulation of nitrite inhalants may predispose abusers to AIDS and Kaposi’s sarcoma." Journal of Neuroimmunology 1998 Mar 15; 83(1-2): 157-161. PMID 9610684

National Toxicology Program "NTP Toxicology and Carcinogenesis of isobutyl nitrite (CAS No. 542-56-3) in F344 rats and B6C3F1 mice (inhalation studies)." National Toxicology Program Technical Report Service 1996 Jul;448:1-302. PMID 12594527 "Under the conditions of these 2 year inhalation studies, there was clear evidence of carcinogenic activity of isobutyl nitrite in male and female F344/N rats based on the increased incidences of aveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma(combined)."

Armenian, HK et al. "Composite risk score for the Kaposi's sarcoma based on a case-control and longitudinal study in the Multicenter AIDS Cohort Study (MACS) population." American Journal of Epidemiology 1993, 138:256-265. PMID

Archibald CP et al. "Evidence for a sexually transmitted cofactor for AIDS-related Kaposi's sarcoma in a cohort of homosexual men." Epidemiology    1992 , 3: 201-209. PMID

Archibald CP et al. Risk factors for Kaposi's sarcoma in the Vancouver Lymphadenopathy-AIDS study.  Journal of AIDS  1990 , 3(Suppl. 1): S18-S23. PMID

Haverkos H et al. Disease manifestation among homosexual men with acquired immunodeficiency syndrome: a possible role of nitrites in Kaposi's sarcoma. Sexually Transmitted Diseases 12: 203-208. PMID

Matur-Wagh U et al. Follow-up at 4 1/2 years on homosexual men with generalized lymphadenopathy.  New England Journal of Medicine   1985 , 313: 1542-1543.  PMID

Matur-Wagh U et al.  Longitudinal study of persistent generalized lymphadenopathy in homosexual men: relation to acquired immunodeficiency syndrome.  Lancet    1984,1: 1033-1038. PMID

Haverkos H et al. "Kaposi’s sarcoma and nitrite inhalants." Adv Biochem Psychopharmacology 1988; 44:165-72. PMID 2899948

Haverkos H et al. "Health hazards of nitrite inhalants." American Journal of Medicine 1988 Mar; 84(3Pt 1):479-82. PMID 2894765

Mirvish SS et al. "Indications from animal and chemical experiments of a carcinogenic role for isobutyl nitrite." Health Hazards of Nitrite Inhalants: NIDA Research Monograph 83 1988 Mar. 83:39-49. PMID 2902514

Haverkos H et al. "Kaposi’s sarcoma and nitrite inhalants." Adv Biochem Psychopharmacology 1988; 44:165-72. PMID 2899948

Haverkos H et al. "Health hazards of nitrite inhalants." American Journal of Medicine 1988 Mar; 84(3Pt 1):479-82. PMID 2894765

Mirvish SS et al. "Indications from animal and chemical experiments of a carcinogenic role for isobutyl nitrite." Health Hazards of Nitrite Inhalants: NIDA Research Monograph 83 1988 Mar. 83:39-49. PMID 2902514

Jorgensen KA et al. " Amyl nitrite and Kaposi’s sarcoma in homosexual men." New England Journal of Medicine 1982 Sep 30; 307(14):893-4. PMID 6125888

Marmor M et al. "Risk factors for Kaposi’s sarcoma in homosexual men." Lancet 1982 May 15; 1(8281): 1083-7. PMID 6122889