The Obstetrician & Gynaecologist 2008;10:1:42-48
doi: 10.1576/toag.10.1.042.27377
Copyright © 2008 by the Royal College of Obstetricians and Gynaecologists.
Recent developments in HIV and women's health
Brenda Kelly, BSc PhD MRCOG, Clinical Lecturer1,
Joanne Morrison, MA DPhil MRCOG, Clinical Lecturer and Subspecialty Trainee in Gynaecological Oncology2 and
Pauline Hurley, BMedSci FRCOG, Consultant and Deanery College Advisor3
1. Nuffield Department of Obstetrics and Gynaecology, Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK brenda.kelly{at}obs-gyn.ox.ac.uk (corresponding author)
2. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford, UK
3. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford, UK
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Abstract
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Key content:- In the UK, the proportion of HIV-positive pregnant women diagnosed before delivery is around 95%.
- The benefits of highly active antiretroviral therapy (HAART) in reducing mother-to-child transmission are undisputed; however, there are potentially adverse effects on maternal and fetal/neonatal health.
- Vaginal delivery may be considered for HIV-positive pregnant women with undetectable viral loads who are on HAART.
- Hormonal contraception can be affected by drug–drug interactions with HAART or nonantiretroviral medication that HIV-positive women may be taking.
- Although HAART can alter the natural history of cervical intraepithelial neoplasia (CIN), annual cervical cytology is still recommended.
Learning objectives:
- To be aware of the different types of HAART, their use and associated maternal, fetal and neonatal toxicities.
- To be able to critically evaluate the place of prelabour elective caesarean section in light of recent developments in viral load testing and HAART.
- To be aware of potential drug–drug interactions that can reduce the efficacy of hormonal contraception in HIV-positive women.
- To appreciate the potential impact of HAART and the recently developed human papillomavirus vaccines on the natural history of CIN in HIV-positive women.
- To know where to find up-to-date information on drug–drug interactions and clinical vaccine trials relating to HIV.
Ethical issues:
- Clear communication about the potential risks and benefits of strategies to reduce mother-to-child transmission is critical to enable HIV-positive pregnant women to reach informed decisions about their care.
Please cite this article as: Kelly B, Morrison J, Hurley P. Recent developments in HIV and women's health. The Obstetrician & Gynaecologist 2008;10:42–48.
Keywords cervical intraepithelial neoplasia (CIN) / highly active antiretroviral therapy (HAART) / HIV / pregnancy / reproductive health
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Introduction
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More adult women than ever are living with HIV: 15.4 million women worldwide are reported to be infected with the virus.1 The majority of these HIV-positive women are in their reproductive years. In western Europe, an estimated 75% of women newly diagnosed in 2005 were aged 15–39 years.2
Developments in HIV medicine have potentially far-reaching consequences for these women. This article aims to provide an update on these advances and their potential impact on the practice of obstetrics and gynaecology in the UK. The impact of these advances in the delivery of care in resource-poor settings is beyond the scope of this present review.
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Developments in HIV medicine and their impact on obstetric practice
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One in every 450 women giving birth in England and Scotland in 2005 was HIV-positive.3 One of the key strategies to prevent perinatal HIV infection in the UK has been the Department of Health policy of ‘opt-out’ HIV testing for every pregnant woman. This has resulted in an increased number of women being aware of their diagnosis before delivery, which has enabled the implementation of effective strategies to reduce mother-to-child transmission of the virus. Since 2003, >90% of all HIV infections in women giving birth in England have been identified before delivery.3 Those remaining undiagnosed are likely to include newly infected or marginalised women. The timely identification of these groups of women continues to be challenging. In addition to improving antenatal education regarding the screening programme and benefits, one solution might be to retest high-risk women who are HIV-negative at booking (for example, where the woman or her partner are from sub-Saharan Africa) later in the third trimester. This selective testing, which has already been endorsed by the American College of Obstetricians and Gynecologists,4 could arguably raise issues about discrimination and is, therefore, best offered to all. Another approach might be to provide rapid HIV testing to all women who arrive unbooked at a delivery suite, which would allow timely institution of post-exposure prophylaxis to babies born to newly diagnosed mothers, as well as counselling regarding the mode of delivery and avoidance of breastfeeding. These interventions, together with antenatal antiretroviral therapy, have reduced rates of mother-to-child transmission to around 1% in the UK (personal communication, P Tookey).
Highly active antiretroviral therapy in pregnancy
The management of HIV in general has evolved with the use of highly active antiretroviral therapy (HAART). These drugs can be divided into three classes (Table 1) and can reduce mother-to-child transmission by:
- reducing viral replication, thus lowering plasma viral load in pregnant women
- pre-exposure prophylaxis of babies by crossing the placenta
- post-exposure prophylaxis of babies after delivery.
Over 95% of pregnant women diagnosed with HIV in the UK now take some form of HAART. As standard treatment, nonpregnant women are now treated with at least three antiretrovirals. Trials in adults have shown that combination therapy is associated with a prolonged suppression of viral replication with marked reductions in viral load, as well as a delay in the emergence of viral resistance. The efficacy of this approach in specifically reducing mother-to-child transmission comes from observational cohorts5 and is supported by a recent Cochrane review.6
The most recent guidelines from the British HIV Association (BHIVA) on HAART in pregnancy7 are outlined in Box 1. There is a clear consensus that women who require HAART for their own health should receive this during pregnancy, both benefiting them and effectively reducing mother-to-child transmission. Where therapy is not required during pregnancy for maternal health, combinations of three or more drugs to suppress HIV replication may be prescribed in the short term to reduce transmission and preserve future maternal therapeutic options. Monotherapy may be an alternative in this group of women if they are also willing to have a prelabour caesarean section as a reasonable alternative to HAART.
Although the beneficial effects of preventing mother-to-child transmission are indisputable, HAART in pregnancy requires careful consideration of possible adverse effects on the fetus as well as the mother. Recent data8 are reassuring with respect to teratogenicity but it should be noted that the sample size is not yet sufficient to explore individual drug combinations or subgroups of abnormalities. A detailed anomaly ultrasound at 21 weeks for all fetuses exposed to HAART in the first trimester is recommended. In addition, all women who receive HAART in pregnancy should be registered prospectively with the Antiretroviral Pregnancy Registry and the National Study of HIV in Pregnancy and Childhood (see Websites). Nucleoside reverse transcriptase inhibitors (NRTIs) affect mitochondrial DNA in patients on treatment for HIV. Evidence of mitochondrial damage or disease has also been demonstrated in a small number of uninfected infants exposed to HAART in utero.9 This has not been confirmed in other large cohorts10,11 but remains an area of ongoing investigation and surveillance. NRTIs also intercalate within host DNA and could, therefore, potentially be involved in subsequent carcinogenesis. No increase in malignancies has been reported in infants exposed to HAART but this may not become apparent for two to three decades.12 A long-term follow-up study of health and development in HAART-exposed children is planned in the UK.13
Table 1 outlines identified short-term maternal toxicities of HAART. Clinicians need to be aware that HIV-positive women who present with signs and symptoms of pre-eclampsia, obstetric cholestasis or other liver dysfunction in pregnancy may well have a gestation-related problem but consideration should also be given to HAART-related side-effects.
Published data,14 based on comprehensive population surveillance in the UK and including 4445 women receiving HAART, demonstrate a significantly increased risk of prematurity associated with HAART. This association, which remained after adjustment for HIV-related symptoms and CD4 cell count as a proxy for maternal health, is consistent with findings from other European cohorts.15,16 There was no detectable relationship between prematurity and duration of HAART exposure, although this may have been due to sample size. The association between HAART and other adverse pregnancy outcomes is unclear: an increased risk of fetal death17 and very low birthweight (<1500 g) has been reported in some studies, but not in others.17–19 Monitoring adverse pregnancy and perinatal outcomes should remain a priority, with further research into mechanisms leading to preterm labour in HIV-infected women.
Prelabour elective caesarean section
Initial studies proposed that a prelabour caesarean section in the presence of intact membranes reduced the risk of vertical transmission. A meta-analysis of 15 prospective cohort studies20 and a randomised controlled trial of mode of delivery21 both supported the protective effect of prelabour caesarean section. Importantly, these studies, which have significantly influenced obstetric practice in the UK, were conducted before plasma viral load testing became routine and included only HIV-1-infected women taking no antiretrovirals or zidovudine only during pregnancy. With the success of HAART in reducing maternal viral load, the added benefit of prelabour caesarean section has been questioned.22 Current guidance in the USA23 states that prelabour caesarean section should be recommended only to those women with a viral load >1000 copies/ml. Recent BHIVA guidelines7 are summarised in Box 2 and suggest that prelabour caesarean section may be unnecessary in selected women with undetectable viral loads on HAART and in those for whom the likelihood of emergency caesarean section for other obstetric indications is low.
These developments present a challenge to the clinical team caring for HIV-positive women who desire vaginal delivery. Plasma viral load may not always reflect activity of HIV in the genital tract24 and this discordance may account for those rare cases of transmission in women delivering vaginally with low or undetectable plasma viral load. There is, however, little information available on how best to monitor genital tract viral load in pregnancy. Current BHIVA guidelines7 recommend avoidance of fetal blood sampling and invasive fetal monitoring, since these may create a portal of entry for the virus. These same guidelines also advocate avoidance of amniotomy, presumably for the same reason. This advice is based on evidence from an earlier meta-analysis,20 which suggested an increased risk of transmission of approximately 2% for every hour of ruptured membranes up to 24 hours. Interestingly, more recent observational studies of HAART-treated pregnant women with low or undetectable viral load do not support these data; with no cases of mother-to-child transmission in babies born by vaginal delivery more than 4 hours after membrane rupture.25 Nevertheless, numbers in these individual studies are relatively small and larger studies with longer follow-up of infants are needed.
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Developments in HIV and their impact on gynaecology practice
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Family planning and fertility
In the era of HAART, HIV-infected women should be assumed to have the same fertility as their HIV-negative counterparts in terms of their ability and desire to conceive.26 Hormonal contraception, in the form of the contraceptive pill, is the most frequently used method of contraception in the UK. Women with HIV infection fall into World Health Organization category 1: they are medically eligible for unrestricted use of the contraceptive pill.27 HIV-positive women using liver enzyme-inducing drugs, including some antiretrovirals, are classified as World Health Organization category 3: the risks outweigh the benefits. Notably, all hormonal methods may be affected by drug–drug interactions with antiretrovirals and appropriate advice regarding family planning options requires up-to-date information about the risk of such interactions (see Table 2 and Websites). In addition to considering the pharmacokinetic evidence relating to antiretroviral agents and hormonal forms of contraception, doctors should also be aware that HIV-infected women may be on other agents that could interact with hormonal contraceptives, such as treatments for tuberculosis (rifampicin, rifabutin), anticonvulsants and herbal remedies (including St John's wort). Given that the greatest number of new HIV diagnoses in the UK is amongst heterosexuals, prevention of HIV transmission should also be considered when reviewing contraceptive options among both serodiscordant and seroconcordant couples. Condoms are the only method of contraception that have been shown to confer a high degree of protection against sexual transmission.
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Table 2
Summary of current pharmacokinetic evidence relating to HAARTand hormonal contraception.51 (Adapted with permission from the Faculty of Sexual & Reproductive Healthcare of the RCOG.)
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Issues in the management of fertility in HIV-discordant and HIV-concordant couples have recently and comprehensively been reviewed elsewhere.7,28
Cervical cancer screening and management of cervical intraepithelial neoplasia in HIV-positive women
Persistent infection with oncogenic human papillomavirus (HPV) serotypes is central to the pathogenesis of cervical intraepithelial neoplasia (CIN) and cervical cancer.29 Immunosuppression, whether by medication or HIV infection, is associated with persistence of human papillomavirus infection and development of CIN.30 Human papillomavirus expresses proteins (E6 and E7), which interact with key tumour-suppressor gene products; this can lead to the transformation of cervical squamous cells and the development of CIN and cervical carcinoma.31,32
HIV-positive women have a higher risk of CIN and subsequent development of cervical carcinoma than their HIV-negative counterparts. In one study33 of newly diagnosed HIV-positive women, 47% had an abnormal smear. A meta-analysis34 of controlled studies concluded that HIV-positive women have a relative risk of 4.9 of having cervical neoplasia (intraepithelial or invasive disease) compared with HIV-negative women. Current national colposcopy guidelines35 recommend that all newly diagnosed women should have cervical cytology and colposcopy performed. HIV-positive women with normal cytology and colposcopy at initial referral should be followed up by annual cytology. HIV-positive women found to have low-grade CIN lesions have a higher risk of progression than HIV-negative women, although not so high that conservative management of low-grade CIN is inadvisable.36 Treatment of high-grade CIN should be by excision of abnormal lesions, rather than destructive methods; the recurrence rate of CIN, however, is high,37 especially in women with low CD4 counts.38
Most large trials on the incidence and progression of CIN were performed prior to the introduction of HAART. More recent studies have examined the effect of HAART on the natural history of CIN. These data suggest that HIV-positive women with persistent human papillomavirus infection are more likely to develop CIN.39 However, HIV-infected women with CIN taking HAART are more likely to have regression of their CIN,40 they are at reduced risk of progression of CIN39 and they are at reduced risk of recurrence following treatment for CIN.41 This regression is thought to be related to HIV RNA expression and CD4 status, suggesting that the beneficial effect of HAART is an indirect effect mediated by the improved immune response to human papillomavirus, rather than a direct effect on human papillomavirus infection.42 However, population studies performed after the introduction of HAART indicate that, although the incidence of other cancers such as Kaposi's sarcoma is reduced, the incidence of cervical cancer in HIV-positive women is increased,43 perhaps reflecting the relatively prolonged natural history of CIN and cervical cancer.
Unfortunately, human papillomavirus, especially in the context of immunosuppression, can cause multifocal disease and co-infection with HIV is not only associated with an increase in the incidence of CIN but also of vulval intraepithelial neoplasia, vulval cancer, anal intraepithelial neoplasia and anal cancer.44
Prophylactic vaccines for human papillomavirus using virus-like particles have been developed for use in young women who are HPV-negative.45,46 As these vaccines are prophylactic, it is unlikely that they will be effective in women who are already HIV-positive, as they may have been exposed to human papillomavirus already. Nevertheless, if in the future a universal vaccination policy is adopted, these vaccines may reduce the incidence of HPV-related CIN in HIV-positive women. Because of the restricted cross-reactivity of human papillomavirus subtypes, it is estimated that these vaccines could prevent 70% of cervical cancers. Cervical screening will still be necessary even in the non HIV-positive population; annual cervical cytology may still, therefore, be recommended for HIV-positive women.
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Future directions
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Although HIV remains one of the principal communicable disease threats in the UK,47 the general public's knowledge of HIV appears to be deteriorating. In a 2005 MORI national survey of knowledge on HIV,48 79% of respondents knew that HIV could be transmitted through unprotected sex, compared with 91% in 2000. The percentage of people who failed to name a single way in which HIV could be transmitted rose from 6% to 8% in 2000–05.48 While HIV prevention programmes, such as strategies to reduce mother-to-child transmission that are focused and adapted to those most at risk of HIV infection, are making inroads, education must not be allowed to slip down the agenda.
Worldwide, the best hope for bringing the epidemic under control remains a vaccine against HIV. The development of such a vaccine is, however, proving to be an unprecedented scientific challenge. The extraordinary power of the HIV virus to mutate at sites in viral proteins that stimulate immune responses and escape almost any means of host attack remains a daunting hurdle to overcome. Several advanced-phase human clinical trials for candidate adenovirus-based vaccines are underway.49 With a growing appreciation of the importance of cytotoxic T lymphocytes in containing HIV replication, efforts are also being directed at developing novel strategies for eliciting virus-specific cytotoxic T lymphocyte responses, with an increasing body of evidence indicating substantial clinical benefits in nonhuman primate model systems. Such an approach allows elicitation of cellular immune responses that can attenuate the clinical disease induced by HIV and contain the spread of HIV, even if they do not actually prevent infection.50 Continuing progress in these areas provides reason to remain optimistic about our ultimate ability to control the spread of AIDS.
Acknowledgements
We are grateful to Dr Pat Tookey, of the National Study of HIV in Pregnancy and Childhood, and Dr Patrick Mallon, of the National Centre in HIV Epidemiology and Clinical Research, Sydney, for discussion relating to HIV medicine and women's health.
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Websites
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Antiretroviral Pregnancy Registry [www.apregistry.com]
National Study of HIV in Pregnancy and Childhood [www.chiva.org.uk/protocols/NSHPC.html]
Faculty of Sexual & Reproductive Healthcare [www.ffprhc.org.uk]
University of Liverpool HIV Drug Interactions Website [www.hiv-druginteractions.org]
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Abstract
Introduction
