The role of progestins in HIV acquisition

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Recent findings have shown that injectable progestin-only contraceptives and high endogenous progesterone use are both associated with an increased number of HIV target cells at the cervix, which may help explain the reported increase of HIV in women with high exposure to progestin, reports Healio.

“Defining the role of injectable progestin-only contraceptives in HIV acquisition is of utmost relevance, particularly in regions of the world where HIV transmission is highest,” Dr Douglas S Kwon, assistant professor at the Ragon Institute of MGH, MIT and Harvard, and colleagues say. “These findings support a role for both endogenous and exogenous progestins in modulating the frequency of cervical target cells.”

Injectable progestin-only hormonal contraceptives are the favoured form of contraception in sub-Saharan Africa, where they are used by more than 8m women, as the contraceptives can be taken discreetly and are available in long-acting formulations that are more than 99% effective, according to the researchers.

Between 19 November, 2012 and 31 May, 2015, Kwon and colleagues conducted a prospective cohort study that included 432 women aged 18 to 23 years who were not pregnant, did not have HIV, and who were living in Umlazi, South Africa, as part of the Females Rising through Education, Support and Health study. The researchers tested for HIV twice weekly and collected demographic and behavioural data as well as blood and cervical samples. They sought to characterise the risk for HIV acquisition associated with injectable progestin-only contraceptive use.

The report says the researchers found that women using injectable progestin-only contraceptives were at higher risk for acquiring HIV and had 3.92 times as many cervical HIV target cells (P = .0241) — specifically CCR5+ CD4 T cells — compared with women using no long-term contraception (adjusted HR = 2.93; 95% CI, 1.09-7.86). In addition, women using no long-term contraceptives in the luteal phase of the menstrual cycle, when the natural progesterone state is the highest, had 3.25 times as many HIV target cells compared with those in the follicular phase (P = .0488). This finding suggests that a naturally high progestin state produced similar immunological changes as injectable progestin-only contraception, according to the researchers.

The risks of injectable progestin-only contraceptives must be weighed against those associated with other contraceptives and communicated to women, the researchers said.

“In areas with both widespread injectable progestin-only contraceptive use and high HIV incidence, including many regions in sub-Saharan Africa, the questions of whether and how injectable progestin-only contraceptives affect HIV acquisition risk are of utmost importance,” Kwon and colleagues wrote. “Decisions regarding the use of injectable progestin-only contraceptives must carefully balance the risk of HIV acquisition with that of unwanted pregnancy.2

The report says in a related editorial, Dr Gita Ramjee, director of the HIV Prevention Unit at South African Medical Research Council, and Dr Sheena McCormack, senior clinical scientist in the MRC Clinical Trials Unit at University College London, wrote that the study by Kwon and colleagues did not sufficiently explain the reason why progestin-only contraceptives increase the risk for HIV.

“The study provides some insight into the biological pathway, but does not sufficiently explain the mechanism for us to understand any differences in risk according to the source of progestin, particularly to differentiate between different methods of contraception,” they wrote.

Ramjee and McCormack suggested that other immune cells, and not necessarily T cells found in the cervix, could play a role in this finding.

Summary
Background
The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract.
Methods
In this prospective cohort, we enrolled HIV-negative South African women aged 18–23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods.
Findings
Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12•06 per 100 person-years, 95% CI 6•41–20•63) than women using no long-term contraception (3•71 per 100 person-years, 1•36–8•07; adjusted hazard ratio [aHR] 2•93, 95% CI 1•09–7•868, p=0•0326). HIV-negative injectable progestin-only contraceptive users had 3•92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0•0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3•25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0•0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives.
Interpretation
Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure.

Full Healio report
The Lancet article summary
The Lancet editorial


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