AIDS TREATMENT UPDATE, Issue 29, May 1995
Robin Gorna

Compared to the quantity of research addressing children or perinatal transmission, scientific research on women is sparse and began very late. In the USA activists have focused attention on the need for greater efforts to research women and HIV, and this conference was part of the fruits of their work.

In summary, this report shows that more is understood about the natural history of HIV disease in women (symptoms associated with the progression of HIV), in particular links with gynaecological symptoms which are extremely common in women with HIV. It is now established that genital pre-cancers are far more common in women living with HIV than in uninfected women, and there is better information on how to screen for these. However, there is a very poor success rate with treatments for genital (pre-) cancers in women with HIV.

The most optimistic news from the Conference concerns developments with technologies to prevent HIV transmission, both sexually and from a woman to her (unborn) child. Although these are not strictly treatment issues, they involve clinical management strategies where scientific advances are strong. HIV-positive women wishing to have babies now have a number of strategies available to them to help reduce the risk of the child acquiring HIV, although there are still no methods which are 100% effective at preventing transmission. Research into a gel which could block sexual transmission of HIV is beginning to show hope, and products are now entering trials. Despite hope in this arena, it may still be several years before such a vital product is approved and commercially available.

NATURAL HISTORY STUDIES

The only way to assess whether or not HIV-positive women develop different diseases from HIV-negative women, and from HIV-positive men, is to conduct studies comparing the disease over time. The natural history of HIV disease in men has been studied from the early 1980s, but concurrent cohorts (groups) of women are now necessary to see if there are any differences. Studies need to compare HIV-positive women with HIV-negative women who have similar histories of drugs use and sexual activity, and the same demographics (e.g. race and socio-economic background). This is because these factors can also have an impact upon health, in particular gynaecological conditions such as menstrual problems and sexually transmitted diseases (STDs). In the US, two large longitudinal studies are now underway to look prospectively at the natural history of HIV disease in women, by monitoring over time how the disease develops. In April 1993 the HIV Epidemiology Research Study (HERS) began enrolling 800 HIV-positive and 400 matched HIV-negative women. The Women's Interagency HIV Study (WIHS) is now enrolling 2000 HIV-positive and 500 matched HIV-negative women.

The initial findings from the natural history studies suggest that HIV does not seem to increase the prevalence of gynaecological problems, with the exception of genital cancers and vaginal candidiasis. Information on menstrual irregularities remains unclear, and it is hoped that future data from HERS and WIHS will give a better sense of whether there are HIV-related differences.

BOX - THE MRC WOMEN'S STUDY

In 1992 a British natural history study was set up with MRC funding to investigate whether the effects of HIV and AIDS in women are similar to those observed in cohorts of men. Known as the MRC Collaborative Study of HIV Infection in Women, its main aim is to monitor clinical outcomes and disease progression in women. It is also assessing the route by which participating women became infected with HIV, and examining how HIV affects womenÆs decisions relating to pregnancy.

Almost 500 women have been recruited to the study at centres in London, Edinburgh, Dublin, Brighton and Portsmouth, and it is continuing to recruit. On joining the study participants complete a detailed questionnaire about their sexual history, and an interview and examination of their medical notes is used to establish their medical history to date. Any developments such as new infections, disease progression or pregnancy are recorded at subsequent routine clinic visits.

GENITAL CANCERS

It is now clearly established that women with HIV are more likely than HIV-negative women to develop genital lesions. These lesions are technically called dysplasias or cervical intraepithelial neoplasia (CIN).

The most common term for these lesions in general use is genital pre-cancer. However, this may be misleading beacuse it implies that these lesions will normally progress to cancers, such as invasive cervical cancer. However, as evidence accumulates it seems that some genital lesions simply remain stable and do not progress to cancer. One optimistic fact is that although genital lesions are very common in HIV-positive women, invasive cervical cancer (ICC) is far less so.

Nearly all women who have genital lesions are infected with the human papilloma virus (HPV), a sexually transmitted disease that can cause genital warts. Genital warts can be diagnosed by clinical examination, but HPV infection is often present even when warts are not. HPV has been linked to genital cancers and is thought to be one of the causes of cancer of the cervix, vagina, vulva, anus and penis. The link between HPV and cervical cancer is not total - other co-factors, such as smoking, are important for the development of disease - but the presence of HPV is an important marker indicating that a woman is at higher risk of developing genital cancers.

Researchers have identified important differences between the various strains of HPV. There are at least 70 different strains of HPV, only a few of which are definitively linked with genital cancers. These are described as oncogenic types - mainly HPV strains 16, 18 and 31. Some strains are associated principally with warts, and are not linked to cancer; these are HPV types 6, 11, 42, 43 and 44. Some researchers in Washington suggested that HIV-positive women should be tested to see which types of HPV they have, so that those with the greatest risk of cancer can be offered more frequent monitoring, but these tests are not routinely available.

One of the major reasons attention had focused so acutely on genital cancers is that ICC is a major cause of death for all women, although women who die of ICC are usually older than the majority of women who develop AIDS. The fear that a high proportion of HIV-positive women would die of cancer does not seem to have been realised. In the expanded AIDS definition adopted in 1993, ICC was listed as an AIDS-defining condition. In Europe in the first nine months of 1994 (the most recent statistics), only 42 women were diagnosed with AIDS because they developed ICC - that is 1.8% of women diagnosed over that timescale.

* Treatment of genital cancers

The worst news of the conference was that invasive cervical cancer (ICC) and its precursor CIN respond poorly to treatment in HIV-infected women. In the general population, genital lesions can be treated and successfully eliminated in around 90% of cases. However, in studies of treatment for HIV-positive women, there is a much greater chance that lesions will recur or progress to cancer, and a success rate of only about 20%.

The fact that lesions do not inevitably progress to cancer may mean that the recurrence of lesions after treatment is not disastrous. For example, one study reported at the conference found that lesions on the vulva frequently recurred despite treatment with trichloroacetic acid (TCA), loop electrosurgical excision (LEEP - a method which aims to remove the whole lesion) or laser. Yet other lesions were not treated at all and did not progress to cancer.

However, if lesions do progress there are no effective treatments for invasive cervical cancer. The poor outcome of interventions means that, especially at low CD4 levels, aggressive efforts to detect and treat genital cancers may be misguided. In an overview of what is known about ano-genital cancers, Joel Palefsky concluded that "Screening and treatment for cervical disease in anybody is not a pleasant procedure. The clinician and the patient need to make choices about how aggressive to be in preventing morbidity and mortality. Where the woman is not going to benefit in terms of prolonged survival or comfort, it may not be useful to continue aggressive screening."

* Screening for genital cancers

Pap smears are tests which involve taking a small scraping of cells from the cervix. These are looked at under a microscope to see if there are any changes in the cells which suggest that cancer could develop in the future. These changes can also be detected using a test called colposcopy. This is a more precise procedure, where a microscope is used to look at the cervix. Colposcopy is often accompanied by biopsy, where a small piece of tissue is cut out for further examination. This can be painful and cause bleeding.

A clinician from Louisiana reported that women who had the most rapid loss of CD4 cells were the most likely to have HPV or to experience progression of genital lesions. The research was based on 48 HIV-positive adolescent women, aged 13 to 21, whose average CD4 count when they entered the clinic was over 500. These results suggest that monitoring the decline of CD4 counts and testing for HPV may be useful early interventions which can alert clinicians to an increasing likelihood of women developing genital lesions.

In addition to cervical cancers, which can be detected by Pap smears, high rates of vulval and vaginal lesions in HIV-positive women were reported. Pap smears may miss the majority of vulval lesions, so colposcopies may be necessary, or at least good physical examinations. The importance of careful external gynaecological examinations of HIV-positive women was stressed, especially for black women where the raised dark lesions may be hard to detect. Ultimately, the issue of detecting lesions is only pertinent if effective treatments are available.

BOX - Colposcopy versus Pap smears

The US guidelines for screening HIV-positive women for cervical cancer state that women should receive Pap smears every 6 months, so long as they have no abnormalities. Abnormalities are investigated using colposcopy. No UK guidance has been issued, but many HIV-positive women report that 6-monthly colposcopies are routine practice at their clinics.

A number of studies have investigated the relative effectiveness of Pap smears versus colposcopies. The key question is whether Pap smears could fail to detect cervical abnormalities that would be detectable by colposcopy, putting women at risk of developing cancer before interventions can be offered.

Research to date has suggested that colposcopy is a more sensitive test for detecting very early pre-cancerous abnormalities that do not yet need treatment. However, Pap smears and colposcopies were equally effective at detecting CIN at the stage that requires treatment in HIV-positive women. Routine colposcopy may therefore be unnecessary.

PROGNOSIS AND SURVIVAL

Early studies of the differences between HIV-positive women and men suggested that women were dying faster, and often before they had received an AIDS diagnosis. Further research suggested that the most important reason for this was likely to be the fact that women with HIV had worse access to medical services in the US (where nearly all the studies were done). This poor access to health care meant that many women were tested for HIV later in their disease, had difficulties acquiring prophylaxis and treatments, and consequently had a shorter survival time.

However, studies have now been undertaken to examine whether the progress of HIV disease in women is different from men when both receive the same standard of care. Overall, it is now established that under these conditions there is no gender-related difference in survival times. However there are some differences in symptoms, for example, it is well known that far fewer women develop KS than gay men _ the only women who appear to develop KS are women from Africa and women who acquired HIV from a bisexual man.

TERMINAL CONDITIONS

Researchers at Cook County Hospital, which treats 80% of Chicago's women with HIV, reported on the first 142 women treated there who died. The 109 women who died of AIDS-related conditions appeared to have a 'normal' disease progress - that is, they had low CD4 cell counts, survived an average of 19 months after their AIDS diagnosis, and 80% had received antiviral treatment or prophylaxis to prevent PCP.

However, 33 of the women in the cohort did not die of AIDS. Most of these women died of complications of chemical dependency (especially related to alcohol), with 6 drug overdoses (some of which may have been suicides) and two women died as a result of domestic violence - one was killed by her male partner, the other by her female partner. There was no matched HIV-negative control group, so it is unclear whether this represents a 'normal' level of mortality among women who were multiple drugs users (which most of these were). The researchers highlighted the importance of ensuring that services are developed for women experiencing domestic violence, and address the range of medical and psycho-social implications of substance use.

BOX - HOSPITALISATION OF HIV-POSITIVE WOMEN

Researchers from Vancouver in Canada analysed levels of hospitalisation of 38 HIV-positive women and 735 HIV-positive men as a way of reviewing access to health care and disease progression. The Canadian epidemic among women is more like the British epidemic than that in the USA û HIV is not so closely connected to poor, drug-using women of colour, and a high proportion of Candian women acquired HIV sexually. Like Britain, Canada also has a universal health service, free at the point of access.

The study found that over a three year period, women had an average of one and a half times the number of stays in hospital that men had. The women who were hospitalised tended to have higher CD4 counts than the men, be younger, and not have AIDS-defining illnesses. Women tended to be more likely to receive AZT monotherapy while men received combination therapies, to be treated by less experienced doctors (who had less than 5 HIV-positive patients) and to be cared for in rural settings. These are all barriers to care, despite women apparently seeking health care more frequently than men. Indeed, it may be that women were in hospital more because of the doctorsÆ lack of experience

CANDIDA

A review of the AIDS-defining illnesses of 175 HIV-positive women and 108 HIV-positive men in Rhode Island found no significant differences between the genders. Overall, the most common illnesses experienced were candida oesophagitis and PCP.

Researchers at the US Centers for Disease Control and Prevention (CDC) compared the AIDS-defining conditions of HIV-positive women over three years, 1990 to 1992. PCP became less common, falling from 49% to 45% to 39%, while other conditions became more common. These were wasting syndrome, rising from 14% in 1990, to 18% in 1991, and 21% of women in 1992, and candida oesophagitis, rising from 12% to 16% to 17% respectively. These data suggest that PCP prophylaxis is an effective intervention for women, but they also indicate that as PCP becomes less common other conditions still need to be prevented from occurring in women living with HIV infection.

A review of CMV disease among people with CD4 counts below 100 found that it is significantly less common in women and male injecting drug users than amongst gay men. By contrast candidiasis may be more problematic among women. There appears to be a hierarchy of candida problems in women, with women first developing vaginal candida at high CD4 counts, and then also developing oral and oesophageal candida as their CD4 cell count falls.

There is a growing problem with strains of candida that have developed resistance to the anti-fungal drug fluconazole during treatment for vaginal candidiasis relatively early in the course of HIV infection. Resistant strains are very hard to treat, although some may respond to alternative anti-fungals such as itraconazole or Amphotericin B (which is toxic and has to be administered intravenously).

To reduce the risk of resistance, some researchers recommend using topical anti-fungal treatments such as nystatin or clotrimazole for vaginal candidiasis. If these fail or candida develops elsewhere in the body, systemic treatments should be used in rotation, with as little fluconazole as possible, in combination with topical treatments.

TREATMENT STRATEGIES

Sadly, very little information was presented at the Conference regarding specific treatment protocols for HIV-positive women compared to men. This was regrettable since there are theoretical reasons to believe that the balance between a drug's effectiveness and its toxicity may sometimes be different in women. The information was not presented principally because it is not gathered in the course of clinical trials.

There are two reasons for this: some trials have excluded women, and those which include women may not analyse their data according to gender. Terry McGovern, a lawyer who was instrumental in the adoption of the 1993 new AIDS case definition, reported changes to clinical trial methodologies which should address this lack of information. On January 19th, the US Food and Drugs Administration (FDA - the agency responsible for approving new drugs) proposed new regulations stating that all trials must analyse their data by gender, and that women may only be excluded from trials where evidence exists that a new compound could harm women's reproductive capacity or put a pregnant woman's fetus at risk.

The fundamental medical differences between women and men with HIV are, inevitably, gynaecological conditions. Researchers need to establish whether symptoms in the genital tract occur with more frequency in HIV-positive women than in HIV-negative women.

Anecdotal reports from women living with HIV have highlighted the fact that there are a lot of gynaecological problems. However, some doctors have questioned whether these problems would have occurred anyway, irrespective of whether the woman had acquired HIV; this is why prospective studies are necessary.

Several studies found that that although many HIV-positive women had previously had STDs, they were rarely seen on examination now. This was attributed to high rates of current safer sex practice, as well as reduced sexual activity following a positive HIV test.

THE MENSTRUAL CYCLE

Menstrual problems have often been reported by HIV-positive women. These include irregular cycles, missed periods, spotting between periods and long or heavy periods. However, one study suggested that there may in fact be no difference between the levels of menstrual problems experienced by HIV-positive women and HIV-negative women in US 'high risk groups'.

The study found that 1.5% of women had over 14 periods in a year, and 20% had less than 10 periods; just over 10% bled for more than 7 days at least once in the past 12 months, and around 3% had at least one period lasting less than 2 days. Just over 10% of the women had bleeding between their periods, 5% had some bleeding after sexual intercourse, and 7% had no bleeding for over 3 months. There were no statistically different rates of problems between the HIV-positive and HIV-negative women, nor were there any noticeable trends towards differences.

What was striking is the overall high level of variation in the menstrual cycle experienced by these women, with just two-thirds of the women having 'normal' menstrual cycles. There were some methodological problems with the study, in particular because it relied on women remembering details about their menstrual cycle over the past 12 months.

PREGNANCY

Researchers have discovered a great deal about HIV and pregnancy, in particular about the risks of HIV transmission to the (unborn) child. There is less information about the impact of pregnancy on the health of HIV-infected women. A number of studies have established that, although pregnancy has an effect on the immune system, it does not worsen the progress of disease in women who are HIV-positive and healthy. There do appear to be some health implications for women who have developed AIDS and take a pregnancy to term, although more research is needed in this area.

Researchers analysed the rate of bacterial infections that women experienced around the time of birth in an American cohort of 160 HIV-positive pregnant women. Over 50% of women with CD4 counts below 200 experienced bacterial infections, compared with 23% of women with counts between 200 and 500, and 12% among those with counts higher than 500. Consequently over 40% of the women with low CD4 counts needed to take antibiotics after birth, compared with 19% of women with counts between 200 and 500, and only 13% of those with the highest counts.

Further information about reducing the risks of transmission was presented. There is now a lot of information available to help women make decisions about pregnancy and reducing the risks of transmission. It is important to emphasise that there are no mechanisms which are 100% effective at blocking transmission, and the data which exists cannot provide firm guidance since it is inevitably preliminary.

* Vitamin A deficiencies

The most intriguing new information concerned vitamin A deficiencies and transmission during pregnancy. 474 HIV-positive women in Malawi were followed during their pregnancy and until the child was one year old, when the child's HIV status was tested. The women were divided into four groups depending on their vitamin A levels, and the HIV transmission rates from woman to child were compared. Transmission rates were 25% among vitamin A deficient women and 32% among very deficient women. Women who had acceptable vitamin A levels had a 16% transmission rate, and only 7% of mothers who had sufficient vitamin A transmitted. Over a quarter of the children died by the end of the first year, and this was also related to the mother's vitamin A deficiency. 93% of the children died whose mothers were extremely vitamin A deficient. The researchers also calculated that vitamin A deficiency doubled the risk of death for the mothers.

The association between vitamin A deficiency and vertical transmission is significant, but it does not necessarily mean that HIV-positive pregnant women should take vitamin A supplementation. High doses of vitamin A can be toxic, and it is a known teratogen - that is, the fetus can be damaged if high levels of vitamin A are taken (over 25,000 international units per day). There are also theoretical concerns that high levels of vitamin A could increase HIV viral replication. There is a clear link between vitamin A deficiency and HIV transmission and higher mortality, but this is not necessarily a causative link. Vitamin A deficiency may be a indication of other nutritional problems, or be a marker for general immune deficiency.

Vitamin A is known to be central to good immune function, and this was further highlighted by research from the US which found more vitamin A deficiency among women with low CD4 counts. They noted that vitamin A deficiency was common among HIV-positive women with counts below 200, especially women who use cocaine. In developed countries, vitamin A deficiency is rare as many food products have vitamin supplementation. Delegates at the conference suggested that 10,000 international units per day of vitamin A is a generally safe level. Overall, the findings from this preliminary research suggest that HIV-positive women who hope to conceive would be well advised to pay attention to their nutritional status and avoid becoming vitamin deficient.

* Viral load in pregnancy

The data from trial ACTG 076 showed convincingly that AZT could reduce transmission to the baby by two-thirds. Although most doctors in the USA seem to have embraced the results enthusiastically, there are important concerns about encouraging all pregnant HIV-positive women to take this potentially toxic drug. Immediately before the conference, there was a meeting of the ACTG network in Washington, and the researchers on 076 presented data looking at the viral load of the women in 076 who transmitted HIV. This, combined with other research presented at the conference, suggests that viral load is a more important factor in transmission than AZT use.

There is nothing revolutionary in the concept that viral load has an important role to play in transmission. Indeed, one of the reasons why AZT was tried was because it reduces viral load. However, the latest findings suggest that the level of viral load is the single most important predictor of HIV transmission from a woman to her child, irrespective of whether the woman takes AZT.

In a new study of 30 HIV-positive pregnant women whose viral load was measured during pregnancy, the eight women who transmitted HIV to their baby were the eight who had the highest viral load detected by PCR tests. These tests were done at several stages during the women's pregnancy and the levels seen early in pregnancy remained relatively stable in women who were taking no antiviral drugs or who stayed on antiviral treatment. This suggests that it may be possible to use PCR to predict the likelihood of HIV transmission from early on in pregnancy. This small study detected no link between using AZT and transmitting HIV, nor between using AZT and the level of viral load.

The research to date has important implications for HIV-positive women. It suggests that a woman who wants to conceive ought to get tested for viral load and if it is high she might choose not to become pregnant (or continue with the pregnancy) at that time. If she has high viral load and continues with the pregnancy the case for using antiviral therapy may be particularly high. To put things back in context, several delegates pointed out that vitamin A supplements cost 2 cents per day, viral load testing is more expensive, but AZT costs a lot more and can be toxic.

MICROBICIDES

Finally, there was hopeful information about new technologies being developed to prevent the sexual transmission of HIV. Women's health advocates have been fighting for years for research to be accelerated to develop a microbicide. A microbicide is a gel, cream or foam that would prevent the transmission of sexually transmitted diseases (including HIV) when placed in the vagina (or anus); it may or may not be combined with a contraceptive spermicide.

There are three basic ways in which microbicide gels could work. First, they may form a physical barrier. Researchers are studying polysaccharides in the hope that they will coat the lining of the vagina and cervix and block the virus in infected cells in semen from attaching to the uninfected mucous membranes. Polysaccharides are large molecules that cannot be absorbed by the genital mucosa, in contrast to chemicals such as nonoxynol 9. Researchers in New York are studying polysaccharides called carrageenans, which are food additives derived from red seaweed; they are used in ice cream and are very safe and non-toxic. In the test-tube, they block HIV from infecting cervical epithelial cells.

Secondly, microbicides could form a pharmacological barrier. Canadian scientists have developed a gel that can line the genital tract and provide a physical barrier to infection. The gel can also incorporate anti-HIV agents such as AZT, ddC or foscarnet. This approach was strongly criticised by some delegates, alarmed at the prospect of introducing potentially toxic drugs into the highly sensitive mucosa of HIV-negative people. Even the scientists conceded that what is known about AZT resistance meant that such an approach is "theoretically crazy".

Finally, microbicides could act as a chemical barrier. The only microbicidal compound currently approved for use in both Europe and the US is the spermicide nonoxynol 9 . It deactivates sperm and STDs and kills HIV in the test-tube. It is used on some condoms and lubricants, but 5-10% of the population are allergic to it and develop inflammation or irritation that may actually increase the risk of transmission. However, other studies have shown that in the absence of these reactions, nonoxynol does reduce the risk of transmission of HIV through unprotected sex. It also kills many other sexually transmitted organisms, whose presence would increase the risk of HIV transmission.

FINDING OUT MORE

The Terrence Higgins Trust and Positively Women recently published 'Positive Women - A Guide to Symptoms and Treatments for Women Living with HIV and AIDS'. The 32-page booklet provides a succinct overview of womenÆs treatment issues. Individual copies are available free from: The Terrence Higgins Trust, 52-54 Grays Inn Road, London WC1X 8JU.

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