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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Monday, January 13, 2003: TOPIC III: HORMONAL INFLUENCES ON HIV DISEASE AND CO-MORBIDITIES

Effect of Contraceptive Methods on Natural History of HIV: Studies from the Mombasa Cohort

Baeten, Jared Ma; Lavreys, Ludoa,c; Sagar, Manisha,b; Kreiss, Joan Ka; Richardson, Barbra Aa,b; Chohan, Bhavnaa,b,c; Panteleeff, Danab; Mandaliya, Kishorchandrad; Ndinya-Achola, Jeckoniah Oc; Overbaugh, Julieb

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aUniversity of Washington, Seattle, WA, USA

bFred Hutchinson Cancer Research Center, Seattle, WA, USA

cUniversity of Nairobi, Nairobi, Kenya

dCoast Provincial General Hospital, Mombasa, Kenya

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Introduction

More than 100 million women worldwide use hormonal forms of contraception, many of whom are at an appreciable risk of HIV-1. Unlike barrier methods of contraception, hormonal methods offer no protection against HIV-1. Some studies have even found that the use of hormonal contraception increases the risk of HIV-11,2 (and reviewed by Martin et al. in this supplement), suggesting that exogenous hormones may have physiological effects that impact virus–host cell interactions and subsequent virus replication. If such effects occur early in HIV-1 infection, then it is possible that contraceptive use at the time of HIV-1 acquisition may also influence the subsequent course of HIV-1 disease. However, it is largely unknown whether factors present at the time of or during early HIV-1 infection, such as the use of contraception, affect steady state levels of virus replication. Because of obvious logistical limitations, few studies have carefully followed HIV-1-infected individuals from prior to HIV-1 acquisition. For the past 10 years, we have prospectively followed Kenyan women at high risk of HIV-1 in a longitudinal study of HIV-1 natural history. Close follow-up in this study has offered a unique opportunity to assess the effect of factors present at the time of HIV-1 acquisition and during the course of infection, such as hormonal contraceptive use, on the natural history of HIV-1 in this setting.

This prospective open cohort study of HIV-1-seronegative female commercial sex workers attending a municipal prostitute clinic in Mombasa, Kenya was initiated in 19932. The principal aims of this study have been to describe correlates of HIV-1 acquisition, virological and clinical characteristics of early HIV-1 infection, and the natural history of HIV-1 disease among African women. At monthly follow-up visits, sexual behavior and contraceptive use are recorded, and laboratory screening for HIV-1 and STI is performed.

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Results

More than 1500 women have been enrolled, and over 3000 person-years of follow-up have been accrued. We have observed 248 seroconversions, for an overall incidence of 8.5 per 100 woman-years. For women who seroconverted to HIV-1, we tested more than 1000 archived plasma samples from all visits after HIV-1 seroconversion as well as from the two clinic visits before seroconversion for HIV-1 RNA (Gen-Probe Inc, San Diego, CA, USA)3. For 161 of these women, we have been able to estimate a date of infection accurately, either because HIV-1 RNA could be detected from a visit before HIV-1 seroconversion (70 women) or because HIV-1 seroconversion occurred within one year of a clinic visit from which samples were HIV-1 seronegative as well as HIV-1 RNA negative (91 women)4. For these latter 91 women, the median time from the last HIV-1-seronegative visit to the first HIV-1-seropositive visit was 93 days. Among the entire group of 161 women, the median time from the date we estimated HIV-1 infection to have occurred to the first HIV-1-seropositive clinic visit was 59 days. These 161 women have been followed for a median of 34 months after the time of infection. For 156 of these women, viral diversity in HIV-1 envelope sequences present during primary infection was determined by a combination of heteroduplex mobility assay and sequence analyses from samples taken an average of 71 days after HIV-1 acquisition5–7.

We used linear mixed effects analysis to model the plasma HIV-1 viral load over time and to examine the effect of factors present at the time of HIV-1 acquisition on subsequent disease progression. The average HIV-1 plasma viral load setpoint, estimated to occur at 4 months after HIV-1 acquisition8, was 4.46 log10 copies/ml (95% CI 4.32–4.60)4. In multivariate analysis, the use of the injectable contraceptive DMPA at the time of HIV-1 infection was associated with a higher setpoint (+0.33 log10 copies/ml, P = 0.03). Multiple viral variants were detected in 89 out of 156 women (57%) and were more common among women who used hormonal contraception (either DMPA or OC) at the time of HIV-1 acquisition (OR 2.7, P = 0.003), compared with women who used no contraceptive method at the time of HIV-1 acquisition9. Women who acquired multiple viral genotypes had a significantly higher viral load (median 4.84 versus 4.64 log10 copies/ml, P = 0.04) 4–24 months after infection compared with women who were infected with a single viral genotype, an effect that persisted during follow-up7. They also had lower CD4 cell counts (median 416 versus 617 cells/μl, P = 0.01) 4–24 months after infection and had a faster decline in CD4 cell counts over time.

Among this group of Kenyan women, the use of hormonal contraception at the time of HIV-1 infection was associated with the acquisition of a more complex viral population, a higher HIV-1 plasma viral load, and a faster CD4 cell decline.

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Conclusion

Our results suggest that hormone use predisposes to the acquisition of a diverse virus population, which in turn leads to higher levels of viral replication and more rapid HIV-1 disease progression. Phylogenetic analysis of a subgroup of women in this study has demonstrated that the diverse viral populations we observed derive from single sexual encounters, rather than superinfection from multiple partners5,6. In addition, this diversity is present even before HIV-1 seroconversion, suggesting a true transmission of multiple viral variants rather than later diversification6. Together, these results suggest that hormonal contraception directly influences the complexity of the transmitted virus population. This presumably represents an increased susceptibility of the host to HIV-1 infection, which is consistent with the observed association between contraceptive use and an increased risk of HIV-1 acquisition1,2.

Although the exact mechanism is unknown, several mechanisms have been proposed for how female hormones may affect HIV-1 infection. These include physiological effects on the integrity of the vaginal epithelium10, an effect on the cell-surface levels of CCR5, which is a key molecule for HIV-1 entry11, or a direct effect on virus expression via hormone response elements within the HIV-1 promoter12. Collectively, the findings suggest that hormonal contraceptive use may not only influence the initial susceptibility to HIV-1 infection, but also early events in viral replication and even subsequent disease progression. More studies are needed to explore the role of hormonal contraception on the rate of generation of viral diversity during chronic HIV-1 infection.

Safe methods of pregnancy prevention are extremely important for women with and at risk for HIV-1. Unfortunately, very little information is available to aid women in weighing the potential risks of hormonal contraceptive use against those of unplanned pregnancy. Our results suggest that hormonal contraceptive use at the time of HIV-1 acquisition leads to higher plasma viral loads and a faster rate of CD4 cell decline. Studies from other populations are needed to confirm these findings, as are studies with clinical outcomes, including progression to AIDS and HIV-1-related mortality. Additional questions include the effect of the initiation and termination of hormonal contraceptive use during chronic HIV-1 infection on subsequent disease, as well as the effect of the total duration of hormonal contraceptive use on HIV-1 natural history. Finally, studies in both developed and developing country settings should be conducted to assess the interaction between hormonal contraception and HIV-1 in the context of antiretroviral therapy.

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Support

This study was supported by theNational Institutes of Health through grants AI-38518, A1-33873, D43-TW00007, T22-TW00001, and subcontract N01-A1-35173-119.

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REFERENCES

1. Wang CC, Reilly M, Kreiss JK. Risk of HIV infection in oral contraceptive pill users: a meta-analysis. J Acquir Immune Defic Syndr 1999; 21:51–58.
2. Martin HL Jr, Nyange PM, Richardson BA, et al. Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1. J Infect Dis 1998; 178:1053–1059.

3. Emery S, Bodrug S, Richardson BA, et al. Evaluation of performance of the Gen-Probe human immunodeficiency virus type 1 viral load assay using primary subtype A, C, and D isolates from Kenya. J Clin Microbiol 2000; 38:2688–2695.

4. Lavreys L, Baeten JM, Kreiss JK, et al. Injectable contraceptive use and genital ulcer disease during early human immunodeficiency virus type 1 (HIV-1) infection increase plasma virus load among women. J Infect Dis 2004; 189:202–311.
5. Poss M, Martin HL, Kreiss JK, et al. Diversity in virus populations from genital secretions and peripheral blood from women recently infected with human immunodeficiency virus type 1. J Virol 1995; 69:8118–8122.

6. Long EM, Martin HL Jr, Kreiss JK, et al. Gender differences in HIV-1 diversity at time of infection. Nat Med 2000; 6:71–75.

7. Sagar M, Lavreys L, Baeten JM, et al. Infection with multiple HIV-1 variants is associated with faster disease progression. J Virol 2003; 77:12921–12926.
8. Schacker TW, Hughes JP, Shea T, et al. Biological and virologic characteristics of primary HIV infection. Ann Intern Med 1998; 128:613–620.

9. Sagar M, Lavreys L, Baeten JM, et al. Identification of modifiable factors that affect the genetic diversity of the transmitted HIV-1 population. AIDS 2004; 18:615–619.

10. Marx PA, Spira AI, Gettie A, et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nat Med 1996; 2:1084–1089.

11. Patterson BK, Landay A, Andersson J, et al. Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission. Am J Pathol 1998; 153:481–490.

12. Hunt JS, Miller L, Platt JS. Hormonal regulation of uterine macrophages. Dev Immunol 1998; 6:105–110.

© 2005 Lippincott Williams & Wilkins, Inc.

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