Despite HIV risk, withdrawing Depo-Provera could increase material mortality

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ContraceptionEven if Depo-Provera and other contraceptive injections raise the risk of HIV infection, withdrawing them from use in African countries would greatly increase maternal mortality, a modelling study has shown. The loss of life due to pregnancy complications and unsafe abortions would far outweigh the number of HIV infections prevented, according to the study.

Observational studies have produced conflicting evidence about a possible link between hormonal contraception – especially depot medroxyprogesterone acetate (DMPA, often marketed as Depo-Provera), a long-acting progesterone-only injectable – and women’s risk of HIV infection. It’s not clear whether an apparent increase in HIV infections reflects a real biological effect of the contraceptive or if the results are skewed by factors which the researchers haven’t been able to fully take into account, particularly differences in the sexual behaviour of contraceptive users and non-users.

Pooling the results of these studies, a recent meta-analysis found that HIV-negative women using DMPA may be at increased risk of acquiring HIV, with a pooled hazard ratio of 1.4 (95% confidence interval 1.2-1.6). More definitive data is likely to come from ECHO, an ongoing randomised clinical trial, which may report results in 2019.

In the meantime, the World Health Organisation recommends that DMPA and other long-acting progestogen-only injectables should remain accessible to women at high risk of HIV, “because the advantages of these methods generally outweigh the possible increased risk of HIV acquisition”. However, women at high risk of HIV who choose to use these methods should be counselled about the possible increased risk of HIV and how to reduce this risk.

The recently published modelling study led by researchers at the department of obstetrics and gynecology, Oregon Health and Science University, Portlandsheds light on the balance of benefits and risks with the use of injectable contraceptives. It focuses on nine countries in sub-Saharan Africa, the world region which has both the greatest burden of HIV and of maternal mortality. In Africa, for every 200 live births, one woman dies during pregnancy, during childbirth or following an abortion. Access to services providing modern contraceptives is poor; around a third of pregnancies in Africa are unintended; and over 98% of abortions are unsafe.

The researchers used a decision-analytic model to assess the potential impact of changing family planning provision (removing DMPA / Depo-Provera and other progesterone-only injectables) in Burkina Faso, Chad, Democratic Republic of the Congo, Kenya, Senegal, South Africa, Malawi, Tanzania and Uganda. The countries chosen reflect variations in maternal mortality, contraceptive mix and uptake, and HIV incidence. They are the countries, say the researchers, “where the balance between benefit and harm is most nuanced”.

For each country, the model incorporated data on HIV incidence, access to HIV treatment, usage of different contraceptive methods, maternal mortality and life expectancy. Country-by-country variation in these factors affected the results.
In line with the meta-analysis, the researchers assumed that injectables are associated with a 1.4 increased risk of acquiring HIV.

The population of focus was women of reproductive age, who did not have HIV and were not planning a pregnancy. The main analysis considered the number of life-years lost or gained. Clearly, a maternal death would be an immediate loss of life. An HIV infection with access to HIV treatment was assumed to result in a 25% reduction in life expectancy. An HIV infection without HIV treatment would result in a 75% reduction in life expectancy.

However, it should be noted that this focus on deaths could obscure attention from the wider impact of poor health. Both living with HIV and having complications in pregnancy could have a long-term impact on quality of life. Nonetheless, the researchers did not use a measure which would reflect this, such as quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs).

The main scenario considered was DMPA being withdrawn, without replacement by equally effective reversible contraceptive methods. In this scenario, considering the nine countries together, for every 100,000 women, there would be 9,000 life-years lost. There was variation between countries, but in all countries the impact would be negative. For example, in Kenya, for every 100,000 women, there would be 6,600 life-years lost. This is largely due to there being an additional 341 maternal deaths per 100,000. While there would be 49 fewer HIV infections per 100,000 women, the decreased use of contraception by women living with HIV would result in 35 additional HIV infections in infants per 100,000 women, so overall there would only be 14 fewer HIV infections a year per 100,000.

Even in South Africa – a country with a very high HIV incidence and relatively low maternal mortality – for every 100,000 women, there would be 1,000 life-years lost. There would be 146 additional maternal deaths per 100,000 women. The 117 fewer HIV infections per 100,000 women would be negated by 114 additional HIV infections in infants per 100,000 women.

An additional scenario considered the effect of replacing DMPA with usage of an equally effective contraceptive, such as an intra-uterine device (IUD) or implant. This analysis found that in all countries apart from South Africa, an unrealistically large proportion of women (over 93%) would need to switch to the new method for there not to be a negative impact on life-years. The researchers say that in any change of family planning provision, significant efforts need to be made to ensure that women find alternative contraceptive methods accessible and acceptable.

“Our model found that removal of POIs (progesterone-only injectables) from the market without effective and acceptable contraception replacement would have a net negative effect on maternal health, life expectancy, and mortality, and this persisted under a variety of modelled scenarios,” the authors conclude. “Policy and programmatic decisions about the role of POIs in family planning programs must therefore be made cautiously, with continued recognition of the interconnectedness of these health issues.”

Objective: The association between increased risk of HIV acquisition and use of progestin-only injectables (POIs) is controversial. We sought to compare the competing risks of maternal mortality and HIV acquisition with use of POIs using updated data on this association and considering an expanded number of African countries.
Methods: We designed a decision-analytic model to compare the benefits and risks of POIs on the competing risks of maternal mortality and HIV acquisition on life expectancy for women in 9 African countries. For the purposes of this analysis, we assumed that POIs were associated with an increased risk of HIV acquisition (hazards ratio of 1.4). Our primary outcome was life-years and the population was women of reproductive age (15–49 years) in these countries, who did not have HIV infection and were not currently planning a pregnancy. Probabilities for each variable included in the model, such as HIV incidence, access to antiretroviral therapy, and contraceptive prevalence, were obtained from the literature. Univariate and multivariate sensitivity analyses were performed to check model assumptions and explore how uncertainty in estimates would affect the model results.
Results: In all countries, discontinuation of POIs without replacement with an equally effective contraceptive method would result in decreased life expectancy due to a significant increase in maternal deaths. While the removal of POIs from the market would result in the prevention of some new cases of HIV, the life-years gained from this are mitigated due to the marked increase in neonatal HIV cases and maternal mortality with associated life-years lost. In all countries, except South Africa, typical-use contraceptive failure rates with POIs would need to exceed 39%, and more than half of women currently using POIs would have to switch to another effective method, for the removal of POIs to demonstrate an increase in total life-years.
Conclusion: Women living in sub-Saharan Africa cope with both high rates of HIV infection and high rates of pregnancy-related maternal death relative to the rest of the world. Based on the most current estimates, our model suggests that removal of POI contraception from the market without effective and acceptable contraception replacement would have a net negative effect on maternal health, life expectancy, and mortality under a variety of scenarios.

Maria Isabel Rodriguez, Mary E Gaffield, Leo Han and Aaron B Caughey


Recent media reports have highlighted the study that voiced concerns that the widely used injection is linked to a possible 40% increased risk of HIV infection. (See MedicalBrief 187). It is thought the hormone contained in the contraception‚ Medroxyprogesterone acetate‚ may suppress the immune system and make it easier for the virus to travel through cells in a women’s genital tract.

But does the three-monthly injection lead to an increased risk of HIV?

The Times reports that the lead researcher on the study‚ US epidemiologist Dr Chelsea Polis said in an interview that it is important to note that a 40% increased risk doesn’t mean a 40% chance of getting HIV.

“Q: Can you explain what increased risk means?
Polis explained: For example‚ based on the current HIV incidence rates in South Africa‚ a woman aged 15 to 24 who is not using Depo-Provera has about a 2.4% chance per year of contracting. If it does increase her risk by 40%‚ then using the hormone would increase her average chances of getting HIV to about a 3.3% chance per year.

“Q: What is the risk for women living in areas of high HIV prevalence?
Polis explained that a woman in a low-income country having condom-less vaginal sex once a week with an HIV-positive male partner‚ who is not using antiretroviral therapy‚ has about a 14% chance per year of contracting HIV. If the injection increases the risk of HIV acquisition by 40%‚ then using the injection would increase her average chances of getting HIV to about 19% per year.

“Q: So what can women do?
According to the World Health Organisation‚ women should be given information on all the benefits and risks of different forms of contraceptives and be advised to use condoms during sex. Polis explained that women should be made aware that Depo-Provera may potentially make her more vulnerable to contracting HIV if she is sexually active and has an HIV-positive partner‚ but the possibility is not 100% conclusive. “She should be assisted to consider what this means in the context of her individual circumstances‚ and should be permitted to decide whether she would prefer to use this option‚ ideally in conjunction with a condom‚ or opt for an alternative method.”

“Q: The evidence of increased risk in humans is not conclusive‚ so what do people make of this? Polis said: “This concern should neither be dismissed as unimportant‚ nor used to cause undue panic by failing to appropriately contextualise the issue or to understand the underlying evidence.”

“Q: What should countries do?
Polis said countries have to weigh up reducing the distribution of Depo-Provera contraceptive injections with the risk of “potential increases in unintended pregnancy and maternal/infant morbidity and mortality”.

Polis on Twitter pointed to the Global Health study, which found it would be too difficult to change all people in sub-Saharan Africa to different contraceptives and maternal mortality deaths would spike‚ as would unwanted children.

The report says in the meantime‚ scientists are awaiting the results of the randomised control ECHO trial being conducted in South Africa‚ Zimbabwe and Kenya‚ which looks at this injection versus two other forms of contraception to see if it leads to an increased risk of HIV.

Aidsmap material
Global Health: Science and Practice abstract
The Times report
MedicalBrief report

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