Treatment

In the last decade, widespread use of combination antiretroviral therapy in Europe and the USA has substantially reduced the rate of progression to AIDS and improved survival. Deaths that included AIDS-related causes decreased from 3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (Palella et al 2006). Six classes of antiretroviral agents are now available — nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, integrase inhibitors, entry inhibitors (or fusion inhibitors) and maturation inhibitors — all of which interrupt the virus’ lifecycle (Figure 64.1). The aim of highly active antiretroviral therapy (HAART), a combination of three or more drugs usually including a protease inhibitor or an NNRTI, is to slow progression of the disease by reducing viral load and thus increasing CD4 count. The British HIV Association has published guidelines on when to start HAART (British HIV Association Treatment Guidelines Writing Group 2008). Efavirenz should be considered as the first-line therapy in all patients, unless the patient is trying to conceive and has primary NRTI or NNRTI resistance. After treatment is commenced, viral load should reach ‘undetectable’ levels, usually less than 50 copies/ml. The CD4 count should rise, with levels below 200 × 10⁶/l representing a significant risk of development of an opportunistic infection. Compliance with HAART regimes needs to be in excess of 95% (Paterson et al 2000) for treatment to be effective and to reduce the chance of emergence of resistant virus.

Transmission

HIV has been isolated in blood, seminal fluid, vaginal secretions, cerebrospinal fluid, saliva, lacrimal secretions and breast milk. The concentration in different body fluids varies. The virus may be transmitted by sexual intercourse, intravenous drug use, transfusion, occupational exposure and vertically from mother to child. The predominant route of infection worldwide is heterosexual sex and, with the great majority of the affected population being in their reproductive years, vertical transmission is an increasing problem. Proper use of condoms is known to greatly reduce the risk of transmission (Heikinheimo and Lähteenmäki 2009). Male-to-female transmission is more efficient than female-to-male transmission, with the mucous membrane of the vagina being more permeable and the surface area being greater, although a partner receptive to anal intercourse is at greatest risk. It is difficult to quantify the risk of sexual transmission ‘per act’ as a constellation of factors are involved, although higher levels of viral load and intercurrent sexually transmitted infection (Wasserheit 1992), particularly ulcerative conditions, in either partner make transmission more likely. Use of barrier methods should also be encouraged in concordant HIV-positive couples to reduce the risk of transmission of resistant virus.

Although transmission of HIV between women who have sex with women (Monzon and Capellan 1987) is very rare, cases have occurred. Use of dental dams (latex barriers) should be encouraged to reduce oral contact with vaginal secretions, and shared sex toys should be cleaned appropriately. Salivary hypotonicity is thought to inactivate HIV-infected lymphocytes, and hence salivary transmission is almost certainly very rare. Oral sex, although less risky than vaginal or anal sex, may result in transmission and this may, in part, be the result of the isotonic nature of seminal fluid overcoming the inactivation of infected cells by hypotonic saliva.

In 2007, approximately 370,000 children under 15 years of age became infected with HIV, mainly through mother-to-child transmission (MTCT). Approximately 90% of infections due to MTCT occurred in Africa where AIDS is beginning to reverse decades of steady progress in child survival. In high-income countries, MTCT has been virtually eliminated thanks to effective voluntary testing and counselling, access to antiretroviral therapy, safe delivery practices, and the widespread availability and safe use of breast-milk substitutes.

HIV testing

HIV testing should be performed with the woman’s consent, and needs only a pretest discussion and consent by a trained healthcare worker. Medical care and support for those diagnosed HIV positive should be arranged immediately after diagnosis. As with all medical care, patient confidentiality should be respected.

There are two methods in routine practice for testing for HIV: screening assay, where blood is sent to the laboratory for testing, or a rapid point of care test (UK National Guidelines for HIV Testing 2008). The recommended first-line assay is one which tests for HIV antibody and p24 antigen simultaneously. These are termed ‘fourth-generation assays’ and have the advantage of reducing the time between the infection and testing HIV positive to 1 month; this is 1–2 weeks earlier than with sensitive third-generation (antibody-only detection) assays. HIV RNA quantitative assays (viral load tests) are not recommended as screening assays because of the possibility of false-positive results, and because they only have a marginal advantage over the fourth-generation assays for the detection of primary infection. Laboratories undertaking screening tests should be able to confirm antibody and antigen/RNA. There is a requirement for three independent assays able to distinguish HIV-1 from HIV-2. These tests could be provided within the primary testing laboratory or by a referral laboratory. All new HIV diagnoses should be made following appropriate confirmatory assays and testing a second sample. Testing including confirmation should follow the standards laid out by the Health Protection Agency (2007).

Point of care tests offer the advantage of a result from either a finger prick or a mouth swab sample within minutes. They have advantages of ease of use when venepuncture is not possible (e.g. outside conventional healthcare settings) and where a delay in obtaining results is a disadvantage, but these must be weighed against the disadvantages of a test which has reduced specificity and reduced sensitivity compared with current fourth-generation assays. Point of care tests are therefore recommended in the following settings:

Although a cure for HIV remains elusive, the advent of effective treatment has resulted in a significantly more optimistic outlook for infected patients. There are clear advantages to knowledge of HIV status, not only in terms of accessing medical monitoring and treatment but also regarding protection of sexual partners and reduction of risk of MTCT. Antenatal testing, previously only offered to women deemed at high risk of infection, is now offered universally as part of routine investigations offered to women in early pregnancy (see below).

The HIV epidemic

More than 25 million people have died of AIDS since 1981. Globally, there were an estimated 33 million people living with HIV in 2007. The annual number of new HIV infections declined from 3 million in 2001 to 2.7 million in 2007. Overall, 2 million people died due to AIDS in 2007, compared with an estimate of 1.7 million in 2001. While the percentage of people living with AIDS has stabilized since 2000, the overall number of people living with HIV has increased steadily as new infections occur each year, HIV treatments extend life and new infections still outnumber AIDS deaths. Southern Africa continues to bear a disproportionate share of the global burden of HIV; 35% of HIV infections and 38% of AIDS deaths occurred in that subregion in 2007. Sub-Saharan Africa is home to 67% of people living with HIV (Joint United Nations Programme on HIV/AIDS 2008).

In 2007, there were an estimated 77,400 persons living with HIV (both diagnosed and undiagnosed), equivalent to 127 persons living with HIV per 100,000 population in the UK (170 per 100,000 men and 84 per 100,000 women). Among 73,300 persons aged 15–59 years living with HIV, 28% are unaware of their infection. A total of 7734 persons (4887 men and 2846 women) were diagnosed with HIV in 2007; a rate of 16 new diagnoses per 100,000 men and nine per 100,000 women. Seventy per cent of the 56,556 persons seen for HIV care were receiving antiretroviral therapy. However, almost one in five HIV-infected persons with severe immunosuppression were not on treatment (Health Protection Agency 2008).

Menstrual cycle

Intuitively, it might be expected that women with HIV, as with any chronic disease, might experience menstrual irregularity or periods of ammenorhoea, perhaps associated with weight loss or deteriorating health. It is certainly true that associated medical problems such as thrombocytopenia may result in menorrhagia, while liver or renal insufficiency may cause amenorrhoea.

While, anecdotally, women with HIV are often said to suffer menstrual disturbance, evidence to support an effect of HIV itself on menstrual pattern is sparse and often conflicting. The consensus is that there is no direct effect of HIV on menstrual pattern, although increasingly disturbed cycles may occur in women with advanced HIV infection who are severely immunocompromised (CD4 count <200) (Harlow et al 2000).

The clinical impression of a high prevalence of an abnormal bleeding pattern may be biased in two ways:

HIV shedding into cervical fluid is lowest in the follicular phase and peaks during menstruation (Reicheldorfer et al 2000), with obvious implications for sexual transmission.

Little information is available on endocrine function in females with HIV. In men, no striking differences have been found when the men are well, but hypogonadotrophic hypogonadism has been reported as a common feature in those who have AIDS. It has been suggested that this may relate to chronic ill health and weight loss rather than to HIV infection itself.

In general, menstrual abnormality should be investigated and treated as in the HIV-negative population, although caution should be exercised when intercurrent disease or treatment affects liver function and may alter metabolism of drug therapy or hormones. In severely immunocompromised patients, abnormal uterine bleeding may be a result of an HIV-related condition, opportunistic infection or neoplasm, and investigation should be tailored appropriately.

Vaginitis

Recurrent vaginal candidiasis is the most common initial clinical manifestation of HIV infection in women (Carpenter et al 1991), and is a problem even at relatively well-maintained CD4 counts. Imam et al (1990) suggested a hierarchy of risk of candidal infection, with recurrent vaginal candidiasis becoming more common with early systemic immunosuppression, oral candidiasis becoming more common with moderate immunosuppression, and oesophageal candidiasis (an AIDS-defining diagnosis) typically occurring with severe immunosuppression. Not only are HIV-infected women more prone to recurrence, but yeasts other than Candida albicans (e.g. Torulopsis glabrata) are isolated more frequently and there is a shorter time before recurrence (Spinollo et al 1994). Response to treatment is usually good, but relapses frequently require retreatment or maintenance therapy.

Pelvic sepsis

Studies of HIV-infected women show no significant difference in the prevalence rates of gonorrhoea and Chlamydia among HIV-positive and HIV-negative women (Minkoff et al 1999). Women with a concurrent sexually transmitted infection are more likely to have a higher viral load in vaginal secretions. Patients should be treated using standard therapy and referred to genitourinary medicine clinics for initiation of contact tracing and follow-up. Pelvic sepsis is probably more common in patients with HIV, but presentation can be varied with less severe symptoms and lesser rises in lymphocyte count, sometimes occurring at the lowest levels of immunocompetence (Korn et al 1993). In general terms, early treatment with standard antibiotics is appropriate and effective.

Syphilis

Syphilis should be treated similarly to HIV-negative patients, although some suggest a value in cerebrospinal fluid examinations before treatment or treatment that will cross the blood–brain barrier as HIV-positive patients may experience neurological manifestations earlier in the course of the disease.

Herpes simplex virus and genital ulceration

Frequency, duration and severity of herpes simplex virus attacks may be increased in HIV-positive women, particularly in immunocompromised women. Attacks may be avoided or treated with oral acyclovir, although resistance can occur, and culture and sensitivity testing is sometimes useful. In resistant cases of genital ulceration, directed biopsy may be necessary to exclude neoplasia.

Genital warts

Human papillomavirus (HPV), usually types 6–11, is common in HIV-infected women and may be more extensive and florid as compared to HIV-negative women. Treatment is along standard lines and, in those with severe immune compromise, resolution may be seen with increasing CD4 count resulting from systemic antiretroviral therapy.

Cervical intraepithelial neoplasia

CIN is common in women with HIV (Adachi et al 1993, Massad et al 1999), and prevalence increases with advancing immunosuppression (Schäfer et al 1991, Johnson et al 1992). HIV-positive women are more likely to be infected with HPV (Palefsky et al 1999), and more of this infection is the result of ‘high-risk’ HPV than in the HIV-negative population. Notably, HPV has been found in women who have sex exclusively with women; therefore, even this population must undergo cervical screening.

Data from the pre-HAART era suggested that CIN was more often of higher grade and more often aggressive in women with HIV compared with seronegative women, and that dysplasia was more likely to persist and progress than in seronegative women (Ahdieh et al 1999). Treatment with HAART may influence cervical dysplasia, although results are not consistent across studies, with some suggesting that women treated with HAART experience early regression of lesions (Heard et al 1998) and others showing no convincing evidence of an effect (Moore et al 2002).

There have been concerns about the usefulness of cervical cytology in HIV-infected women, and the optimal method and frequency of screening of this population remain unresolved. Larger studies have validated the use of cervical cytological screening combined with a low threshold for colposcopy and directed biopsy. The guidelines of the Royal College of Obstetricians and Gynaecologists advocate annual smears for women with HIV with no history of abnormality. Screening intensity should continue unaltered in women with excellent CD4 and viral load responses to HAART. High-grade cervical lesions should be treated appropriately, whilst women with low-grade abnormalities who are likely to adhere to follow-up may safely be monitored on a 6-monthly basis. The clinical usefulness and cost-effectiveness of HPV typing incorporated in routine clinical practice in women with HIV remains uncertain.

Cancer of the cervix

This diagnosis is a gender-specific AIDS diagnosis added to the AIDS definition in 1993. In the UK, there has not been a great rise in the number of cases of cervical carcinoma in HIV-positive women, and this may represent either effective screening or long latency of the disease, with more effective antiretroviral therapy likely to play a role. One study has shown that 2.5% of HIV-positive women aged 15–49 years in European countries have presented with this malignancy as a first AIDS-defining event (Serraino et al 2002).

Other genital neoplasias

Vulval and anal intraepithelial neoplasias have also been reported more commonly in HIV-infected women (Williams et al 1994), although the possible role of screening has not been evaluated.

Antiretroviral therapy

If the mother is not yet on HAART but requires antiretroviral therapy, this should be given in accordance with the British HIV Association guidelines for non-pregnant women. Some women choose to defer treatment until after the period of organogenesis after discussion with their HIV physician. Women already taking HAART will often choose to continue their therapy, although uncertainty regarding the long-term effects of intrauterine exposure to antiretrovirals at any gestation may be a cause for anxiety.

In developed countries, most studies have shown a transmission rate of 15–25% in the absence of treatment, but the use of antiretroviral therapy in pregnancy has reduced transmission rates significantly. Use of AZT (a nucleoside) monotherapy was a breakthrough in reducing vertical transmission (Connor et al 1994). AZT commenced prior to the third trimester, given to the mother intravenously during delivery and given to the neonate orally led to a decrease in transmission by 67% in a placebo-controlled trial. AZT monotherapy does not reduce viral load to undetectable levels, and so does not prevent vertical transmission solely by an effect on viral load. Its precise mechanism of action remains uncertain. For this reason, although AZT monotherapy is still a regime recommended by the British HIV Association, there is a trend towards use of short-term antiretroviral therapy (START) regimes (combination therapy taken from approximately 28 weeks of gestation for the duration of the pregnancy), even in mothers who do not require antiretroviral therapy for themselves (i.e. who have a CD4 count >350). Unlike AZT monotherapy, START regimes aim to reduce viral load to undetectable levels to reduce levels of transmission as much as possible.

The potential for simplified regimes has been assessed, and neviripine (an NNRTI) monotherapy given in two doses, one to the mother during labour and the other to the neonate at 48–72 h, has been shown to be more effective than a single dose of AZT in Africa (Guay et al 1999). However, evidence of subsequent neviripine resistance (which will compromise effective treatment regimes available to the mother) continues to emerge and use of neviripine monotherapy is generally not advised.

Obstetricians should be aware of possible side-effects occurring in women receiving antiretroviral therapy. Protease inhibitors may lead to glucose intolerance and an increasing likelihood of gestational diabetes, whilst two of the nucleoside agents (DD1 and D4t) have been associated with the development of lactic acidosis (three fatal cases), which may mimic the haemolysis–elevated liver enzymes–low platelets syndrome. These agents should probably be avoided if possible. Those women with greater immune compromise may be taking antibiotic prophylaxis against opportunistic infection. Septrin, the agent most commonly used, is a folate antagonist, and prescription of folate supplements should prevent developmental abnormalities.

All women should be registered prospectively on the Anti-retroviral Pregnancy Registry (managed by GlaxoSmithKline), set up to monitor short- and long-term side-effects. Women and their children should also be registered with the Royal College of Obstetricians and Gynaecologists and the British Paediatric Surveillance Unit. Efavirenz (an NNRTI also known as DMP) has been shown to cause a range of defects of varying severity in cynomolgus monkeys, and its use should be avoided if at all possible. In counselling women in this area, it is important to weigh up the uncertainty regarding toxicity against the undisputed benefits of preventing vertical transmission.

Delivery route

In the majority of cases, transmission occurs at the time of delivery; however, this will occur in utero in a small percentage of cases. There is now conclusive evidence to recommend prelabour lower segment caesarean section. A meta-analysis of 15 prospective cohort studies showed a 50% reduction in transmission (International Perinatal HIV Group 1999), and a 70% reduction was found in the European controlled trial (European Mode of Delivery Collaboration 1999). There is uncertainty regarding whether there is a persistent benefit in caesarean section when the mother has an undetectable viral load (<50 copies/ml).

Breast feeding further increases the risk of transmission of HIV by between 7% and 22% (Dunn et al 1992). In the developed world, the majority of postpartum transmission is the result of breast feeding, and its avoidance significantly reduces rates of infection (Kreiss 1997). If a woman decides to breast feed despite this evidence, she should be advised to breast feed exclusively as transmission rates are highest when mixed feeding is employed. There may well be considerable cultural difficulties around not breast feeding, and women need support and advice regarding how to deal with this.

Transmission rates

Transmission rates of between 1% and 2% can be achieved by a combination of antenatal treatment with antiretrovirals, AZT infusion at a prelabour caesarean section, avoidance of breast feeding and infant antiretroviral therapy. Treatment and follow-up of the infant should be undertaken by a specialist paediatric team.

Contraception

All patients should be advised to use barrier contraception to protect against transmission of HIV, transmission of resistant HIV, other infections and pregnancy. Many women decide to use a ‘belt and braces’ approach, using an additional method to reduce the risk of unplanned pregnancy further, although there is some evidence that condom use declines in HIV-positive women who use combined oral contraception (COC). Women taking antiretroviral therapy which may induce or suppress liver enzymes to varying degrees should be made aware of the possible risk of subtherapeutic levels of their COC pill, and advice to use condoms as well should be reinforced. Those using depot injections and taking HAART should have injections every 10 weeks. HAART regimes containing protease inhibitors have been associated with elevations in blood triglycerides and cholesterol, which should be monitored closely in those taking COC.

Previous advice was for women with HIV to avoid use of intrauterine devices because of potential risks of infection and a possible increase in risk of transmission to male partners resulting from increased duration and heaviness of menses. This has not been substantiated (European Study Group on Heterosexual Transmission of HIV 1992), and this may well be a method of choice in carefully selected candidates (Sinei et al 1998). The progestogen intrauterine system is increasingly used for women with HIV, with the benefits of excellent contraception and a reduction in blood flow.

Sterilization should be undertaken following the same guidelines as apply to other women. However, care needs to be taken around the time of diagnosis of HIV, when women have not had sufficient opportunity to adjust to the diagnosis and may subsequently regret the procedure.

Spermicides, such as nonoxynol-9, appear to inactivate HIV in vitro but may not be so effective in vivo. Unfortunately, there is evidence that nonoxynol-9 may cause mucosal inflammation that might lead to an increased risk of HIV transmission. The contraceptive implant Implanon has not been evaluated in these women, although it is likely to play a role. All women should be aware of emergency contraception (Levonelle and emergency intrauterine device insertion) and where this can be accessed.

Termination of pregnancy

Women requesting termination of pregnancy should be referred to an appropriate clinic where both medical and surgical options may be offered as appropriate. As for HIV-negative women who have had unprotected sexual intercourse, sexually transmitted infection screening may also be appropriate at this time.

Planning pregnancy

Any woman planning pregnancy should be advised to stop smoking and reduce alcohol consumption, and folate supplements should be prescribed. It is sensible to assess the woman’s overall state of health, and in the HIV-positive woman, this will include checking recent levels of viral load and CD4 count. HAART regimes containing a known teratogen such as efavirenz should be altered if possible.

Both partners may be HIV infected or only one. Where only the woman is infected, the entirely safe method of artificial insemination using the partner’s semen can be employed. Advice should be given regarding the timing of ovulation and the optimum time of insemination, with some women preferring to buy commercially available ovulation predictor kits.

An HIV-negative woman may have an HIV-positive male partner. HIV does not appear to infect sperm directly. Therefore, if sperm can be isolated from the white blood cells and the seminal plasma in a ‘sperm-washing’ procedure, it should be possible to inseminate a woman safely. Semprini et al (1992), Gilling-Smith (2000) and Marina et al (1998) have experience of more than 3000 cycles of sperm washing and intrauterine insemination or in-vitro fertilization (resulting in 300 live births) with no reported seroconversions. The sperm-washing procedure is expensive and not currently freely available, and some couples may decide to pursue ‘unsafe’ insemination with unprocessed semen or to practice ‘unsafe’ sex. Mandelbrot et al (1997), however, have published results of a study of 92 HIV-negative women whose partners were HIV positive and who had 104 pregnancies. All couples had unprotected intercourse during the fertile period as determined with commercial ovulation predictor kits. There were only four seroconversions, all in couples who did not use condoms consistently during the rest of the cycles.

Even when both partners are infected with HIV, condom-free intercourse cannot be recommended because of the possibility of transmission of resistant virus. Couples may choose to perform, possibly less risky, home insemination.

Infertility

This has been a contentious but important area. Women and their partners should not automatically be denied access to treatment because of HIV infection. As with HIV-negative women with potentially life-shortening conditions such as complicated diabetes, post transplant or a history of cancer, HIV-infected women must be equipped with information and allowed to make their own reproductive decisions (Gilling-Smith et al 2001).

Continuing childlessness can be extremely distressing, and factors such as current state of health and long-term prognosis, support networks and motivation to pursue often stressful investigations and treatments should be discussed and counselling given. Advice regarding HIV, treatment and prevention of vertical transmission should be accurate, up to date and given in conjunction with expert HIV physicians.

Infertility may present in a number of different situations with one or both partners being infected with HIV. Where in-vitro fertilization is necessary, the possible emotional and financial costs should be discussed, and this treatment should only be carried out where there are provisions to perform treatment safely and without risk of infection to others.

Occupational transmission to healthcare workers

Most occupational transmission has occurred following needlestick or other sharps injuries, and there have been a very few documented seroconversions after contamination of broken skin or mucous membranes. The risk of acquiring HIV from a single accidental parenteral exposure to infected blood has been estimated at approximately 0.3%. Those performing surgical procedures should employ universal precautions, bearing in mind the prevalence of undiagnosed HIV and hepatitis B and C infection. The last two conditions are much more readily transmitted than HIV. A woman with HIV should not be subjected to any unnecessary and discriminatory infection control procedures which could isolate her or draw attention to her before other patients or relatives.

Postexposure prophylaxis

Immediately after a percutaneous or mucous membrane exposure to potentially HIV-infected blood, thorough washing with warm running water and soap and clinical evaluation of the injury should be performed. Any bleeding should be encouraged. Consultation with local HIV experts should be as rapid as possible in order that appropriate prophylactic antiretroviral therapy can be commenced, preferably within 1 h, to reduce the risk of seroconversion (Department of Health 2000).

HIV-infected healthcare workers

The Department of Health (2000), Medical Defence Union and UKCC [United Kingdom Central Council for Nursing, Midwifery and Health Visiting (now Nursing and Midwifery Council, NMC)] are clear that HIV-positive health workers should not take part in invasive ‘exposure-prone’ procedures, and the individual should inform their occupational health department of their status. In addition, the General Medical Council recommends that staff who think they have been at risk should be tested confidentially.