British HIV Association, BASHH and FSRH Guidelines for the Management of the Sexual and Reproductive Health of People Living With HIV Infection 2008

A. Fakoya; H. Lamba; N. Mackie; R. Nandwani; A. Brown; E.J. Bernard; C. Gilling-Smith; C. Lacey; L. Sherr; P. Claydon; S. Wallage; B. Gazzard

Disclosures

HIV Medicine. 2008;9(9):681-720. 

In This Article

4.0 Sexual Dysfunction in HIV-positive Men and Women

Men and women commonly report sexual difficulties in the presence of HIV. These range from the loss of desire to difficulties in establishing and maintaining partnerships, to specific EDs.

4.1 Erectile Dysfunction: Investigation and Management

ED is a common problem and the prevalence increases with age.[77] There is a small amount of evidence that HIV-negative MSM are more likely to present with an erectile problem.[78,79] However, there have been many reports of an increased prevalence of erectile difficulties in HIV-infected MSM,[79,80,81,82,83,84,85] which may contribute to unsafe sex practices.[81] The precise reasons for the increased rates appear complex, and may be physical or psychological in origin. And whether the ED predates infection has not been studied. Although one study[86] identified only PIs as an associated factor, other studies have confirmed a higher prevalence in patients not on HAART or on non-PI-containing combination therapy regimens.[79,83,84]

The European Association of Urology has recently updated guidelines on the investigation and management of ED[87] and other recommendations have been published in the British Medical Journal.[88] An overview of the management of HIV-infected men with erectile problems was also published in 2002.[86,89] In the management of any sexual dysfunction, it is important to make an assessment of the sexual relationship(s) and the need for psychological interventions for either one or both partners.

Although the management of ED is not significantly altered by HIV infection per se, it is important to be aware of other major contributing factors. Psychological problems, concomitant drug therapy (such as anti-depressants, anti-psychotics, anabolic steroids, megestrol, lipid-lowering agents) and recreational drugs (including anabolic steroids, alcohol and psychoactive substances) have all been implicated.[90] Neuropathy and atherosclerotic disease from any cause, but especially diabetes mellitus, may manifest as erectile failure.

The first-line agents recommended to manage ED, unless contraindicated by concomitant nitrate therapy, are the orally active phosphodiesterase inhibitors type 5 (PDE5Is): namely sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra). All these agents appear efficacious, although patients may have a preference for one drug, and all are predominantly metabolized by the liver by cytochrome P450 3A4.[91] Interactions with erythromycin, ritonavir and ketoconazole have all been reported and shown to increase significantly the drug levels of sildenafil or other PDE5Is.[92] Therefore, other drugs that inhibit this system may be predicted to have a similar effect and should be used cautiously (including all PIs, other macrolides but not azithromycin[92] and some other anti-fungal agents). The lowest starting dose is recommended and titrated according to response and side effects. Most recently, a study confirms that if sildenafil is taken with darunavir (boosted with ritonavir), dosing should be at 25 mg over a 48-h period. Based on these findings, it is suggested that the vardenafil dose should not exceed 2.5 mg in a 72-h period and that the tadalafil dose should not exceed 10 mg in 72 h[93] (www.hiv-druginteractions.org).

No studies on the effects of the currently licensed NNRTIs (efavirenz, nevirapine) on PDE5Is have been published, but inducers of cytochrome P450 might be predicted to reduce levels and higher doses of PDE5 inhibitors may be required to achieve a clinical effect. The currently unlicensed investigational NNRTI, TMC278, does appear to significantly decrease plasma sildenafil concentrations, and a higher PDE5I dose may be required if used concurrently.[94]

Patients who use amyl nitrate or other recreational nitrate agents should be cautioned not to use these agents in conjunction with PDE5Is.

A study by Sherr et al.[95] has shown that there is no increase in risk behaviour in the presence of sildenafil itself, but that those who use sildenafil also tend to be higher users of other risk-related substances (drugs and alcohol) - suggesting that some people have added PDE5Is to a risk-taking profile rather than the PDE5I per se triggering HIV-related risk behaviour. The relationship between high-risk behaviours, possible HIV transmission and PDE5I use has been highlighted recently in the USA.[96] Access to PDE5Is by non-conventional methods (Internet prescribing) does not normally allow for a proper discussion on safer sex, or discussion around safe use of these drugs with recreational agents.

No significant drug interactions with ARV agents have been described with other currently available classes of drugs used to treat ED.

Use of intracorporeal alprostadil is very effective, but needs careful explanation for correct use and to prevent priapism, and may not be acceptable to the patient. Furthermore, because the injection site may expose partners to blood-borne microbes (such as HIV, HBV, HCV and syphilis), patients should be counselled to ensure that a condom is rolled back to cover the injection site. Safe needle disposal also needs to be addressed. Alprostadil is also available as a trans-urethral preparation. It may cause local side effects including urethral pain and have a less reliable clinical effect, but may be more acceptable than administration by injection.

4.1.1 Key Points and Recommendations.

  • There is some evidence that men living with HIV infection are more likely to experience erectile difficulties, which may adversely affect effective condom usage and should be treated.

  • There are important drug interactions between PDE5 inhibitors and PIs, which may necessitate dose modification of the PDE5 inhibitor.

  • Recreational drug use may affect condom use and erectile function, and needs to be assessed. Inhaled nitrates are contraindicated when using PDE5 inhibitors.

  • A full recreational drug history is an important part of the assessment of ED. Patients should be counselled on safer sex, possible drug interactions and contraindications to PDE5 inhibitor use.

4.2 Other Male Sexual Dysfunctions

Although ED is the most common sexual dysfunction in men, other problems including ejaculatory problems (premature/rapid ejaculation and retarded ejaculation), loss of libido and arousal problems can occur.

4.2.1 Ejaculatory Disorders. There is little evidence that rapid ejaculation is more common, although there is evidence that drug-induced peripheral neuropathy may result in retarded ejaculation.[90] Guidelines on the management and investigation of rapid (premature) ejaculation and retarded (delayed) ejaculation have been published by BASHH.[97,98] Retarded ejaculation in the context of neuropathy may be extremely difficult to treat, and may be exacerbated by concomitant use of anti-depressants to treat the neuropathic pain, but it may have a psychological cause.[81]

4.2.2 Loss of Desire. Problems of loss of sexual desire have been described at high prevalence rates in HIV-infected men, affecting 41-48% of seropositive MSM.[79,98] Although hormonal abnormalities can affect desire and have also been described in patients on ARVs,[81,83,99,100] no causal link has been established firmly; the individual often cites psychological reasons as the putative cause.[81,98] However, a review of medications that may cause hormonal disturbance (sex steroids, prolactin and thyroid hormones) and signs of hypogonadism, together with hormonal assays, is warranted to determine if a physical cause can explain the symptom.

There is some data to suggest that men on HAART have increases in serum oestradiol, which may be a cause of loss of sexual desire[79,81] and may respond to testosterone therapy (unpublished).

With HAART, and with the reduction in the prevalence of late-stage HIV disease, it is likely that the prevalence of hypogonadism has decreased.[100] However, the prevalence of hypogonadism increases with age and it is likely that this entity will still be clinically relevant.

Furthermore, in a recent study in 296 HIV-positive men in the USA, researchers found that 17% of the men had low testosterone levels and another 16% had borderline levels - an increased prevalence relative to the general population.[101] Low plasma testosterone was related to increased age, advanced HIV, higher body mass index and lipodystrophy. All hypogonadal individuals in this study had evidence of a central origin with decreased follicle-stimulating hormone and luteinizing hormone. Sixty-three per cent of those patients who received androgens reported satisfaction with this therapy.

However, analysis of a cohort of men with sexual problems published in 2006[96] did not show hypogonadism to be a common finding (although raised oestradiol was), despite low sexual desire being a common presenting complaint. A questionnaire survey of HIV-positive MSM in another central London clinic[102] showed that 41% of sampled men (14/34) use anabolic steroids 'recreationally', and this exogenous source might lead to an underestimate of the problem of hypogonadism, or even be a cause of it acutely on cessation (because of suppressed testicular production).

Secondary hypogonadism warrants estimation of other hormones [cortisol, thyroid stimulating hormone (TSH), prolactin (PRL)] and magnetic resonance imaging of the pituitary fossa (particularly if there is hyperprolactinaemia), and referral to an endocrinologist should be considered.

Although androgens have been used for the treatment of HIV-related wasting and for chronic hypogonadism, many questions remain unanswered, including those regarding the long-term effects (if any) and hence safety. Known side effects include hepatic dysfunction, polycythaemia, acne, testicular atrophy, male pattern baldness and gynaecomastia.

Transdermal patches, gels, muco-adhesive sustained-release buccal tablets and long-acting intra-muscular testosterone esters are designed to provide testosterone levels that are approximate to normal physiological levels, in order to improve patient acceptability, reduce adverse events and to further increase the number of treatment options available. In patients with chronic hypogonadism, forms of testosterone replacement that provide stable physiological levels of testosterone may be preferable to those that result in supra-physiological levels. However, some of the topical preparations can cause local irritation and the patient may prefer injections.

There is the potential for inducers of cytochrome P450 3A4, such as ritonavir, to increase the levels of some androgen preparations (www.hiv-druginteractions.org).

Men with androgen-dependent cancers such as prostatic carcinoma should not receive testosterone supplementation.

4.2.3 Key Points and Recommendations.

  • Guidelines for the management of rapid and delayed ejaculation have been issued by BASHH and other organizations;[90,98] these should be consulted for guidance (IV).

  • Peripheral neuropathy (of any cause) may manifest as retarded ejaculation, and therefore may occur in patients with HIV or on certain ARV agents (III).

  • Lowered sexual desire may have a psychological basis (in both men and women) but warrants hormone measurements to exclude an organic cause (III).

4.3 Women and Sexual Dysfunction

Very little has been published on sexual dysfunction in women, and even less in the context of HIV infection. Therefore, the body of evidence in terms of specific management guidance in this context is sketchy. Furthermore, a recent study suggests that women with HIV are rarely asked by their treating physician(s) about female sexual dysfunction (FSD)[103] and therefore problems are presumably under-diagnosed and under-treated.

There are reports of high prevalence rates in women with HIV[104,105,106,107] and this may be greater, at least in the pre-HAART era, than the rate in the general population.

There may be a psychological, physical or mixed basis to the presenting difficulty, but in general FSD usually relates to psychosocial issues and the HIV diagnosis itself. Morphological changes associated with ART may cause body image problems as well as stigma. Fear of onward transmission (horizontal or vertical) may be a major cause of anxiety and dysfunction, particularly where there may be disclosure issues, and a need to negotiate condom use.[103]

It is important that women are asked about any problems and an appropriate history and examination is performed before they are referred to a healthcare provider with expertise in FSD.

Organic causes of FSD are comparable to organic male dysfunctions and may be caused, for example, by neuropathy (HIV- or drug-induced), endocrine disturbances or atherosclerosis.[104]

4.3.1 Key Points and Recommendations.

  • FSD is often under-reported and under-treated. Healthcare providers should be mindful of this when caring for women with HIV (III).

  • Where a problem is identified, an assessment should be made and the patient should be referred if necessary (IV).

  • Psychological issues are often a key component to such problems (III).

4.4 HIV, Cervical and Anal Pre-cancers and Cancers

4.4.1 Cervical Intraepithelial Neoplasia (CIN) and Cervical Screening.4.4.1.1 Introduction. Both cervical cancer and the pre-invasive lesion of the cervix (CIN) are significantly more common in HIV-positive women compared to HIV-negative women.[108,109] The risk of having CIN in the setting of HIV appears to be related to the degree of immunosuppression.[107,110] The development of cancer of the cervix from pre-invasive lesions can take up to 10 years in immunocompetent women; this factor forms the basis of cytological screening programmes, which target the detection of such pre-invasive lesions. It is clear that cytological screening is as effective in HIV-positive women as it is in HIV-negative women.[107]

Since 1993, invasive cervical cancer in HIV-positive women has been classified as an AIDS-defining illness.[111] World-wide, cervical cancer is the second most common cancer in women,[112] although rates vary from country to country and depend on endemic rates, life expectancy following HIV diagnosis and access to routine screening, with the highest rates in developing countries. HIV-infected women have more aggressive and advanced disease and a poorer prognosis.[113]

4.4.1.2 Role of Human Papilloma Virus. The role of HPV in the pathogenesis of cervical cancer and CIN is now well established.[114] Studies have led to the classification of HPV types according to oncogenic risk.[115] It is known that HIV-positive women have a higher prevalence of cervical HPV infection than HIV-negative women and this is further increased in women with lower CD4 cell counts.[116] HPV infection is also more persistent in HIV-positive women,[117,118] particularly with the more oncogenic types.[118]

Because HPV is known to be an aetiological agent of cervical cancer and present in nearly all women with high-grade CIN, testing for high-risk HPV has been proposed as a method of improving cervical screening. Molecular techniques for the identification of HPV DNA are highly sensitive and specific. Patients and providers may be reassured with negative HPV testing but long-term management of positive HPV testing (especially in conjunction with negative cytology) is unclear. HPV testing in routine clinical practice is therefore not recommended until more data are available.

A quadrivalent prophylactic HPV vaccine (HPV 6/11/16/18; Gardasil®, Merck, Whitehouse Station, NJ, USA) has recently been licensed in the USA for use in women. There are no current data around safety or efficacy for such vaccines in HIV-positive patients, and studies are awaited.

4.4.1.3 Impact of HAART on Cervical Disease. There have been dramatic reductions in morbidity and mortality related to HIV following the introduction of HAART.[119] Because women live longer in the post-HAART era, there is potentially a longer time for the progression of disease associated with CIN. HAART has the potential to improve immune function and possibly facilitate clearance of HPV, thereby inducing regression of CIN or prevention of CIN development. However, the evidence for this has been inconsistent to date. Other factors such as cellular genetic changes (which are not influenced by HAART) may well play a key role in the development of disease. Data available on the natural history of HPV-related cervical disease in HIV-positive women prior to the introduction of HAART indicate that spontaneous regression occurs rarely.[120,121] Heard et al.[122] found that despite regression of CIN with HAART there was persistence of HPV. A further Italian study noted no effect on HPV following initiation of HAART,[123] although follow-up in both of these studies was limited. The data on the effect of HAART on CIN are variable, with some studies showing a benefit in terms of CIN regression[124] and others showing no positive impact.[125] The paucity of definitive data means that current screening guidelines for CIN in HIV-positive women should not be modified if women are receiving HAART.

4.4.1.4 Cervical Screening in HIV Infection. Because of the high prevalence of CIN and cervical HPV infection in HIV-positive women, CIN should be aggressively screened for and treated. Guidelines for the NHS Cervical Screening Programme[126] currently recommend that all women newly diagnosed with HIV should have cervical surveillance performed by, or in conjunction with, the medical team managing the HIV infection. Annual cytology should be performed with an initial colposcopy if resources permit. Subsequent colposcopy for cytological abnormality should follow national guidelines, although immediate referral to specialist colposcopy services following an initial abnormal smear (mild dyskaryosis) is advised based on the frequent persistence of CIN in HIV-positive women. The guidelines also suggest that the age range screened should be the same as for HIV-negative women, i.e. first invitation at 25 years and ending at 65 years. There are few data regarding the prevalence of cervical lesions in sexually active HIV-positive adolescents who may have been immunosuppressed for many years. Therefore, there may be a need for more intense surveillance on a case-by-case basis.

4.4.1.5 The Use of Newer Techniques for Cervical Screening. Liquid-based cytology (LBC) is now the preferred technique for cervical screening and is recommended by the NHS Cervical Screening Programme (NHSCSP)[126] and NICE. This technique is currently being rolled out nationally across the NHSCSP. These newer Pap smear screening techniques using liquid-based media appear to increase sensitivity and decrease inadequate smears; they also offer the ability to perform direct HPV testing on collected specimens. They are more expensive and there are no current data examining the utility of these tests in HIV-positive women.

Some data suggest that in high-risk populations, the sensitivity of LBC may be no greater than the sensitivity of conventional cytology.

Guidelines for cervical cancer and CIN screening will continue to evolve as knowledge of the pathogenesis of the disease as well as the role of HPV expands.

4.4.1.6 Key Points and Recommendations.

  • All newly diagnosed HIV-positive women should have a sexual and gynaecological history as part of their initial medical assessment including cervical cytology and a sexual health screen if appropriate (III).

  • Advanced HIV disease is the strongest independent risk factor for developing cervical abnormalities. All abnormal smears (mild dyskaryosis) should be referred to specialist colposcopy services (II).

  • Annual cytology is recommended for all women living with HIV to detect cervical pre-cancer. The result of each smear should be documented in the HIV case notes regardless of where the test is carried out (including those performed in community settings) (II).

  • The management of CIN in HIV-positive women should not differ from that in the general population (III).

  • There are limited data on the effect of HAART on the natural history of disease and so management of women should be the same whether they are receiving therapy or not (II).

4.4.2 Anal Cancer

4.4.2.1 Epidemiology. Cancer of the anus and anal canal was recorded in England and Wales in 2003 at incidence rates per 100 000 population of 1.2 in men and 1.7 in women.[127] In the general population, anal cancer mortality rates are about 30% of these.[126] However, men and women with HIV infection have a much higher risk of anal cancer than the general population. For example, US national data showed relative risks (RRs) of invasive anal cancer for men and women with HIV infection of 37.9 and 6.8, respectively.[128] However, receptive anal intercourse is a very strong risk factor for anal cancer in both HIV-negative and HIV-positive men, and the degree of excess risk associated with HIV infection in MSM at the present time remains unclear.[129,130] [Although anal cancer shows a strong association with a history of receptive anal sex in men (RR 33.1, 95% CI 4.0-272.1), in women the association is weak or non-significant (RR 1.8, 95% CI 0.7-4.2)].[131] Data from the entire Chelsea and Westminster Hospital (London) HIV-positive cohort showed rates of anal cancer of 60/100 000[132] between 1984 and 2003, which was 120 times higher than an age-, sex- and regionally matched control population.[132] Higher rates of 92/100 000 were recorded in the post-HAART era (1996-2003) compared to the pre-HAART era, but this difference did not reach statistical significance. Patients were treated with combined modality chemoradiotherapy.[133,134] The 5-year overall survival was 47%, and the 5-year disease-free survival was 66%. There was no difference in overall survival between pre- and post-HAART eras.

4.4.2.2 Natural History. Anal cancer shows many similarities to cervical cancer in that HPV infection is the causative factor in most or all cases. Somewhat less is known about anal cancer to date, but for cervical cancer it is now accepted that HPV is a necessary cause. Two recent series that conducted HPV typing of anal cancer specimens reported HPV positivity rates of 83% and 81% (all men), 95% and 88% (women) and 98% (MSM).[135,136] Most of these HPV infections were with 'high oncogenic risk' (HR) HPV types such as HPV 16, 18, 31, 33, 35, etc. However, 'low oncogenic risk' HPV types such as HPV 6 and 11 can be detected alone in a small minority (∼ 2.5%) of anal cancers.[137,138] It should be noted that current cigarette smoking is also a significant risk factor for anal cancer, both in men [odds ratio (OR) 3.9, 95% CI 1.9-8.0] and in women (OR 3.8, 95% CI 2.4-6.2).[135]

HPV is a very frequent STI that is usually asymptomatic. Prevalence rates of anal HPV infection in HIV-negative MSM are 50-60% across all age groups.[139] Most anogenital HPV infections are transitory, resolving spontaneously within ∼ 9 months, although longitudinal data on anal HPV infections in HIV-negative MSM are sparse to date. In general, persistent HPV infections are more frequent in persons over 30 years of age and the immunosuppressed. A quadrivalent prophylactic HPV vaccine (HPV 6/11/16/18; Gardasil®, Merck) has just been licensed in the USA for use in women, but whether it will be effective in men and whether HIV infection may abrogate vaccine-induced protection are not known at the present time.

The anal canal has a transformation zone (TZ) at the junction of the anal squamous and rectal columnar epithelia,[140] similar to the cervix, and thus anal cancer probably arises because of HR HPV infection of metaplastic reserve cells in the anal TZ, which have a higher propensity to oncogenic transformation. However, receptive anal sex is not a pre-condition for such HR HPV infection and neoplasia of the anal canal, as shown by the occurrence of anal neoplasia in men and women with no history of receptive anal sex.[141]

Anal neoplasia shows many parallels with cervical cancer, and a spectrum of anal pre-cancerous changes referred to as anal intra-epithelial neoplasia (AIN) is seen.[139,142] AIN can be classified as in the original Richart CIN classification, i.e. AIN 1, AIN 2, AIN 3, where AIN 3 is full-thickness anal mucosal pre-cancerous change, or using the more recent Bethesda system where the terms low-grade or high-grade squamous intra-epithelial lesion (LSIL = HPV/AIN 1, HSIL = AIN 2/3) are used and where cytological and histological diagnoses are likely to be more reproducible. Unlike cervical cancer, where we know that women with CIN 3 have a ∼ 30% progression to invasive cancer over 10 years, there are no formal natural history studies of AIN 3 demonstrating progression rates to anal cancer. However, there is no doubt that such progression occurs, as evidenced by individual case observations, by the usual finding of invasive cancer within surrounding AIN3 and the overwhelming HR HPV 'smoking gun' evidence. However, the frequency of progression is not accurately known, although a figure of ∼5% overall is sometimes quoted on the basis of progression rates of perianal Bowen's disease.[137,138]

Natural history studies of anal pre-cancer in HIV-positive MSM have been conducted in the pre-HAART era.[143,144] Persistent HPV was associated strongly with progression from normal to HSIL (P = 0.0001): 24% of men normal at baseline progressed to HSIL over 4 years, and such progression was more frequent with lower CD4 cell counts.[145]

4.4.2.3 Are there Tests that can Detect Anal Pre-cancer? Anal warts are encountered frequently in clinical practice, and can be problematic to treat. Ano-genital warts are caused by HPV 6 and HPV 11. Recent studies using sensitive PCR methodology have detected either HPV 6 or HPV 11 in ∼ 100% of genital wart lesions, but have also shown that genital wart lesions are frequently co-infected with HR HPV types - especially in HIV-infected individuals, where co-infection rates of up to 100% are seen.[143] Thus when anal warts are present AIN can be frequently detected concomitantly. In a study of 47 men with anal condylomata, where 79% of men were HIV-positive and where random biopsies from each anal canal quadrant were taken, these biopsies showed 16/47 (34%) to have AIN 2/3 and 3/47 (6.4%) to have invasive cancer.[146]

AIN affecting the peri-anal skin, perineum or natal cleft can produce symptoms of itching and soreness. It also often produces recognizable clinical signs of pigmentation, white lesions, fissuring, etc. If there is ulceration, tests for herpes should be carried out. Diagnostic punch biopsies should be carried out if there are physical signs suggestive of AIN, or persistent ulceration.

However, when AIN alone affects the anal canal there are usually no symptoms and often no overt clinical signs. Occasionally AIN can be suspected on naked-eye inspection, manifesting as white plaques or red lesions. When invasive cancer is present there may be symptoms of soreness and bleeding, and there are signs of ulceration or induration.

'Sub-clinical' AIN can be diagnosed through cytology, anal colposcopy (also referred to as high-resolution anoscopy; we will arbitrarily use the term colposcopy) or histological examination of biopsy specimens. Nowadays, cytology is usually performed using liquid-based technology; many series attest to its utility.[140,145,147] Colposcopy uses techniques that are similar, but distinct, to those used for the examination of the cervix.[126] After visualization of any aceto-white areas, local anaesthetic can be infiltrated using a dental syringe and forceps (e.g. Tischler's) used to take small biopsies. One issue that is similar for the cervix is the accuracy and reproducibility of these various diagnostic techniques. All have downsides: cytology tends to under-call diagnoses compared to biopsy,[139,144,145,146] colposcopic-directed biopsies may miss the worst histological lesion[146] and histopathological reporting may be inaccurate.[148]

Various ancillary tests could be proposed for the diagnosis of AIN; these need further research and evaluation. HPV tests, in particular the detection of high-risk HPV types, seem a logical proposition; in reality, these are too sensitive and have a very low positive predictive value.[146] Tests with good operational characteristics for the detection of AIN 3 would be ideal. There are a number of new candidates for such an approach, including tests for cell cycle proteins such as p16INK4a, which can be performed on LBC samples.[149]

4.4.2.4 Are There Treatments for Anal Pre-cancer, and are they Effective? The current definitive treatment for CIN 3 is excision of the cervical TZ. Unfortunately, the anatomy and complex physiology of the anal canal precludes any similar approach. The anal mucosa also surmounts only a narrow bandwidth of sub-mucosa before deeper fundamental structures are encountered, and thus excision or ablative surgical therapies performed on minority areas of the mucosa have to be restricted to the superficial layers, and excision of too extensive an area can result in the serious consequence of anal stenosis. Perhaps because of these difficulties, a variety of treatments for AIN have been described.[141,150,151] These include treatments that are evidence-based for genital warts, including podophyllotoxin, trichloracetic acid, imiquimod and electrosurgery, although the evidence base for using these treatments for genital warts in HIV-infected individuals is much smaller. However, at present the number of published trials that have actually examined treatments for AIN systematically is tiny.[152,153] There is a particular dearth of data on the outcomes of the medical therapies referred to earlier.

Chang et al.[152] described the outcomes of a single out-patient electrosurgical treatment of AIN 2/3 during the period 1995-1999 performed with sedation and often a field block. In HIV-positive men over a mean follow-up of 29 months, 23/29 (79%) developed a recurrence of their disease. Goldstone et al.[153] described the outcomes of out-patient infrared coagulation therapy of localized AIN 2/3 in HIV-positive men performed under local anaesthesia during the period 1999-2003. Recurrent disease developed in 44/68 (65%) at a median time of 7 months. Second and third re-treatments were administered for recurrent disease, after which the overall prevalence of persistent disease was 40% at 14 months. It has been suggested that even when surgical therapy for AIN has been conducted and disease has relapsed/recurred, the incidence of subsequent invasive cancer may be 75% lower than in an untreated individual.[154] Although this could be possible, there are no data to justify the assertion.

There has been debate over whether the use of ART affects the prevalence of AIN. A recent study of 92 HIV-positive men used multivariate regression analyses to evaluate risk factors for histological AIN (all grades), and concluded that nadir CD4 cell count was a significant risk factor (OR 2.0, 95% CI 1.1-3.3) and that current use of ART was protective (OR 0.09, 95% CI 0.01-0.75).[155] Larger studies would allow similar analyses restricted to AIN 2/3.

4.4.2.5 Current Uncertainties on Systematic Testing for Anal Pre-cancer in HIV-positive Men and Women. There are many issues in this area, even with respect to terminology. The term 'screening' should be properly used to describe the application of a preventive technology to an entire population, or a defined sub-set of that population. For example, it could be proposed that all homosexual men in the UK population were offered screening for anal cancer. However, we believe this would not be practicable, deliverable or desirable, and is also outside the remit of these guidelines. However, when it is proposed that a particular preventive technology is applied to a defined group of patients, it is more accurate to describe such an application as systematic testing. Thus we will discuss whether systematic testing for anal cancer and its precursors is warranted in HIV-infected individuals, and specifically in the sub-groups HIV-positive MSM, heterosexual men and women.

There are already wide differences of opinion in this area. Whereas one group concluded that testing HIV-positive MSM with anal cytology every 2 years 'offers quality-adjusted life expectancy benefits at a cost comparative with other accepted clinical preventive interventions',[154] another group concluded that 'more information is needed on the recurrence rates of high-grade AIN and the relative morbidities for the various techniques before widespread screening programmes can be implemented'.[155]

There are a number of fundamental uncertainties and issues to be resolved in this area:

  1. The rate of progression from AIN 2/3 to anal cancer in the three HIV-positive sub-groups (MSM, women and heterosexual men) is not known.

  2. Existing data concerning treatments for AIN 2/3 are very limited with large uncertainty factors. Much more research is needed, including prospective studies of existing therapies, new approaches to therapy - including combination treatments and novel therapies (e.g. therapeutic vaccines) - and determining whether such therapies actually decrease subsequent cancer risk.

  3. Given the current lack of knowledge concerning progression rates and the outcomes of treatment, is there justification for triage based on any anal cytological abnormality triggering anal colposcopy and biopsy? If current practice really only delivers early detection of invasive lesions, would anal cytology and prospective follow-up alone deliver similar benefits?

  4. If patients with HIV are delivered accurate information about existing knowledge and lack of knowledge in this area, including risk/benefit of the various possible screening/triage/conservative or therapeutic management strategies, what is the acceptability of the various potential strategies in the three HIV-positive sub-groups (MSM, women and heterosexual men)?

4.4.2.6 Key Points and Recommendations.

  • All major HIV units should develop clinical guidelines for the management of suspected anal cancer and pre-cancer (IV).

  • All major HIV units should develop either local clinical expertise or referral pathways for suspected anal cancer and pre-cancer (IV).

  • The role of annual anal cytology and anoscopy is not yet proven; however, patients should be encouraged to check and report any lumps noticed in the anal canal (IV).

4.5 Psychological Aspects of HIV and Reproduction

The desire to conceive and parent is universal. There is good evidence that this is affected but not altered by the presence of HIV infection, for both women and men. The availability of HAART has changed the views on reproduction of both men and women.

4.5.1 Psychological Issues of HIV and Reproduction. These can be summarized by understanding behavioural factors and emotional responses linked with:

  • safer sexual behaviour to prevent transmission of HIV to others, risk behaviours and behavioural patterns;

  • pregnancy and HIV;

  • fatherhood issues;

  • emotional health.

4.5.2 Safer Sexual Behaviour to Prevent Transmission of HIV to Others: Risk Behaviours and Behavioural Patterns. There is a considerable literature on risk behaviours and HIV prevention. Earlier studies have focused on HIV prevention among HIV-negative persons or those of unknown HIV status. More recently, the importance of positive prevention has been highlighted and provides a particular need for those treating HIV-positive people. A number of reviews have examined the trends in risk behaviour and adoption of safe behaviour and interventions to promote safety and reduce risk. General findings show that HIV risk continues[156] and counselling interventions (with follow-up booster sessions) can effectively reduce risk behaviours (and subsequent STI infections).[157,158] Community-based interventions have some effects,[159] while there is evidence for and against the efficacy of peer programmes.[160]

4.5.3 Pregnancy and HIV. Psychological considerations are relevant in relation to:

  • HIV issues for all pregnant women;

  • reproductive issues for all HIV-positive people, such as:

4.5.4 Ante-natal HIV Testing. The availability of interventions to dramatically reduce infant infection has prompted the wide-scale introduction of ante-natal HIV testing for all pregnant women. There are clear guidelines on integrating HIV discussions into routine ante-natal care.[161] The standards of counselling, informed consent and support should not be compromised in pregnancy. For many women, HIV testing in pregnancy may be the moment they discover their positive status. Thus all such programmes should have clear links into routine HIV provision prior to initiating any generalized ante-natal screening. In the UK the majority of women will test HIV-negative, and the occasion of the HIV test can be used to promote HIV prevention in future. The UK Department of Health advises a routine offer of HIV testing in pregnancy. Different centres have trained all midwifery staff on HIV issues, appointed an HIV-specific midwife or counsellor, integrated HIV testing into the routine battery of tests on offer in ante-natal care or made specific efforts to address HIV (especially in areas of higher prevalence such as London). Uptake rates of HIV testing in such environments are high (in excess of 80% in many London clinics), and the corresponding drop in HIV-positive infants has been notable. Most women who find out their HIV status during pregnancy take up the basket of interventions on offer (ART to prevent mother-to-child transmission, Caesarean section and avoidance of breast feeding). Treatment choice and decision-making is a complex process. This is enhanced by the presence of continuity of care, providing a dedicated carer knowledgeable in HIV and an opportunity to explore options and revisit decisions.

Couple testing and couple counselling are seen as cost effective,[162] yet women-only counselling is more common in the UK. The literature clearly shows some neglect in responding to and catering for the needs of fathers who are equally affected at such times. HIV-positive men (both homosexual and heterosexual) have reproductive concerns and find it difficult to raise these in clinics.[163] These concerns should be discussed with HIV-positive men and women.

4.5.5 Family Planning and Termination of Pregnancy. HIV provision in family planning and termination clinics lags behind ante-natal provision, with little rationale. Ideally, services should make such testing routinely available for all family planning and termination clinic attendees.[164]

4.5.6 Counselling Around HIV Testing. The widespread increase of HIV testing, specifically with routine offers of testing in ante-natal clinics, has raised the profile of HIV and acted as a cornerstone in the HIV response. The role of HIV testing in prevention is also well established. All those attending for voluntary counselling and testing (VCT) should be counselled on contraception and safer sex as well as prepared for HIV testing. Quality counselling has been shown to be effective.[165] In many settings brief, perfunctory counselling is all that is possible. This is good for gaining informed consent and notifying people of service provision but may not be the most effective in achieving behaviour change or emotional preparation. Services should have in-house provision or have systems of referral available as part of the planning process when setting up ante-natal HIV testing provision.

In reproductive health, men are rarely included in HIV testing and counselling provision while the service for women varies. Evidence suggests that male services are not provided, although the literature suggests that it should be made available and integrated into services.

4.5.7 Ethics on Fertility Treatments. People with HIV may experience fertility problems and may have difficulty accessing fertility treatments. There are well-documented emotional sequelae (for both men and women) of infertility. Furthermore, the process of fertility treatment may bring anxiety and emotional upheaval.

4.5.8 Parenting in the Presence of HIV. People with HIV have general parenting concerns as well as those particularly added by the presence of HIV in one or both partners. The level of burden and the nature of concern are often altered by the HIV status of the child. Goldstein et al.[166] noted that approximately 20% of HIV-positive parents in the USA had parenting concerns (no similar figures exist for the UK). Psychological distress, anxiety and depression are common (over 30% screen positive). Supportive cohabiting partners act as a buffer to such stresses. Issues to be mindful of include:

  • Depression around HIV testing, during pregnancy and post partum.[167]

  • Adherence: parents (particularly mothers) prioritize their child's HIV care over their own in terms of clinic attendance and other variables.

  • Decision making: many decisions have to be made by HIV-positive parents, including the decision to conceive, treatment options and parenting decisions. The availability of ART has had an impact on such decisions and the risk of vertical transmission plays a key role in these decisions.[168,169]

  • Custody plans: planning for the future is challenging for parents with HIV and is noted for being a slow and unstable process. Rotheram-Borus[223] found that 44% of parents died without custody plans, and that parents frequently changed their plans - the majority of which involved family members.

4.5.9 Developmental Issues. It is well established that mental health factors in parents affect child development. There is no reason to believe that these findings do not relate to HIV. Furthermore, there are direct and indirect effects of HIV on child development. These are often mild but noticeable. Mechanisms are unclear, with contributions from the virus itself (on HIV-positive children), illness, school absence, hospitalization, medication side effects, parental illness/absence/death and educational/learning opportunities that are affected by stigma and trauma. Clear ongoing family programmes are needed to support and provide for the needs of families in the presence of single or multiple HIV.

4.5.10 Fatherhood Issues. It is trite to assume that reproduction should be focused totally on women. Men - homosexual and heterosexual - have needs and roles in relation to reproduction and fathering. Many men who have been exposed to HIV through a same-sex relationship may still have fatherhood issues, may indeed have sought fatherhood, or may have emotional needs in relation to procreation. Heterosexual men are also involved in fathering.[162] Fatherhood desires are high, although some studies show that in couples with HIV there may be differences in desires.[170] Studies of HIV-positive men desiring children show that men anticipate disapproval, believe they would experience discrimination, are rarely provided with full and adequate information and would like referral to fertility services.[171] Decision-making, help-seeking and resource provision should be made available to men as well as women.

4.5.11 Emotional Health. SRH, fertility and infertility issues and relationships are all emotionally laden experiences. The mental health literature notes that progressing through care may often result in raised anxiety, mood fluctuation, depression and emotional pain. Furthermore, there is some evidence that heterosexual men with HIV are less likely to be referred to mental health provision.[152] There may be additional anxiety linked to the medical process and procedures; this may be exacerbated by the clinical approach, which is often viewed as cold and mechanical in what is emotionally and physically a very different experience for individuals and couples. Good communication, adequate time and acknowledgement of emotions should be seen as an adjunct to care provision. For a proportion of people with reproductive or sexual health issues, referral to counselling, clinical psychology or psychiatry may be appropriate. Good service provision should establish links, liaison and referral pathways as an integrated part of care.

4.5.12 Key Points and Recommendations.

  • Psychological considerations are of key importance in several issues including conception and HIV in pregnancy, sexual behaviours to reduce HIV transmission and sexual functioning.

  • All units involved in HIV service delivery should consider the funding and provision for mental health and the behavioural aspects of SRH.

  • An updated understanding of HIV prevention, risk behaviour, reproduction and mother/father perspectives should feed into policy and service provision.

4.6 HIV Sexual Transmission and HAART

4.6.1 Introduction. There have been several advances in the field of HIV transmission science that have implications for the counselling and clinical management of PLHA. Patients need evidence-based information and advice in order to make important decisions in developing and maintaining long-term meaningful relationships.

In general, and in short-term casual relationships, advice and support on safer sex and the use of condoms to reduce the transmission or acquisition of HIV or other STIs is still recommended.[172] However, couples in long-term monogamous relationships may wish for information in order to make decisions about whether or not to cease using barrier protection. This may be for couples who are either sero-different or sero-same.

There is currently no UK guidance on counselling on HIV transmission in the era of HAART; it is envisaged that because this is an increasingly important and controversial area, detailed guidance will be developed in the near future. In the interim, we present the currently available evidence, which may be useful in guiding consultations and discussions.

4.6.2 Risks of HIV Transmission on HAART. Studies have shown that the risk of HIV transmission correlates with the level of plasma HIV RNA for sexual[49,173] and mother-to-child[174,175] transmission. It is now well established that treatment with HAART reduces HIV infectiousness.[35,176] Extrapolations from epidemiological and biological data have led Swiss experts to the opinion that individuals with chronically suppressed viral loads taking HAART and with no STIs are not sexually infectious if certain key criteria are met.[177] The Swiss experts state that viral load suppression must be for at least 6 months and that the person must be on effective suppressive therapy under regular clinical follow-up.

Although the precise transmission risk on suppressive ART is not known, prospective studies have shown no transmissions between sero-different couples if viral loads were undetectable.[50,178] Similarly, during therapy the concentration of HIV diminishes in both semen[37] and cervico-vaginal fluid.[35,38] Mathematical modelling of transmission data by Chakraborty et al.[179] shows that as the viral load in semen reduces, the transmission rate per sexual act reduces exponentially to approach zero. Although there is compelling evidence to reach similar conclusions to the Swiss where oral and vaginal intercourse are concerned, gaps exist in currently available evidence regarding the transmission risk of anal intercourse - which is practised not only by MSM but also by a significant minority of heterosexuals, who may be unwilling to disclose this to healthcare workers. There would also be concern about the interpretation of this statement by individuals who might make decisions about their infectiousness based on incorrect assumptions, e.g. about the presence of STIs if they were asymptomatic, or who have multiple casual partners.

Nevertheless, providing information on HIV transmission to HIV-positive individuals is vital, and clear information based on the evidence must be provided in ways where the possibility of ambiguity does not arise. Time should be made available for detailed counselling and information provision, which can support PLHA to develop and maintain healthy and fulfilling sexual relationships, including the choice of procreation. Key areas of discussion are included as follows with a summation of the evidence to date in each case.

4.6.3 HIV Transmission Between Two HIV-positive Individuals. In a situation where both partners in a sexual relationship are HIV-positive, the potential risks of unprotected sexual intercourse include the transmission or acquisition of other STIs and the possible transmission or acquisition of a second strain of HIV - superinfection. The extent to which superinfection occurs is not known but evidence from the literature suggests that it is uncommon.[180,181] With the availability of ART, the main detrimental consequence of superinfection is acquisition of resistant virus.[182] The relevance of superinfection is important in two situations. Firstly, several sexual, HIV harm-reduction strategies have arisen in the era of ART, particularly in the homosexual community. These include disclosure of HIV status and serosorting of partners, so that those with the same status may engage in unprotected anal intercourse. Secondly, specialized conception services are limited;[183] sero-same partners wishing to conceive are often faced with the dilemma of whether to consider unprotected intercourse.

4.6.4 HIV Superinfection. Multiple infections can occur at three distinct phases of HIV disease. They can occur during primary infection (known as simultaneous infection) if two different strains of HIV infect the same cell. They can also occur after primary infection but before the immune system has produced antibodies to HIV (in the 'window period'). This has been termed sequential infection. Infection with two or more different viruses at this stage is termed dual infection. However, if re-infection occurs once HIV has become a chronic infection, this is known as superinfection.

4.6.4.1 Timing of Superinfection. Research in both primates[184,185] and humans suggests a 'window of susceptibility' to superinfection with most infections occurring shortly after primary infection. Up to 24 cases of apparent superinfection in HIV-infected individuals have been reported.[186,187,188] In most of these cases, the second virus appeared within the first three and a half years of HIV infection. However, in two cases, the second virus may have appeared up to 12 years after initial infection.[162,164,165,189]

4.6.4.2 Risk of Superinfection in Recent HIV Infection. The risk of superinfection may be relatively high during the first few years of infection; in fact, the majority of case reports of apparent superinfection have been within the first year of infection. Smith et al.[182] found a 5% incidence rate of HIV-1 clade B superinfection within 6-12 months of initial infection among recently infected homosexual men with frequent partner change. Similarly, Grant et al.[190] estimated a first-year apparent superinfection incidence rate amongst recently infected homosexual men of between 2.1% and 8%. The lower estimate reflects the overall cohort, about 50% of whom did not report HIV exposure after initial infection. The higher estimate reflects those men for whom an exact timing of first infection was known and who reported continued HIV exposure after initial infection.

Taken together, these data suggest that the rate of superinfection during the first year of HIV infection may be comparable to the overall incidence of new HIV infections seen among high-risk populations.

4.6.4.3 Risk of Superinfection in Chronic HIV Infection. No apparent superinfection cases have been reported among chronically infected individuals - either untreated or on ART - in cohort studies. Gonzales et al.[180] looked for superinfection in 718 people (representing 1072 person-years of follow-up), the majority of whom were on ART, in a clinic cohort and found no evidence of it. However, no data on continued HIV exposure were reported. Tsui et al.[181] documented high-risk behaviour among injecting drug users over 215 person-years of observation and also found no evidence of superinfection. There was no evidence of superinfection among HIV-positive couples with genetically distinguishable virus at baseline after 233 person-years of follow-up, representing an estimated 20 859 exposures during unprotected anal or vaginal intercourse. Based on self-reported risk behaviour, they calculated that they would have expected to see 89 new infections during this time if one of the partners had been HIV-negative.[181]

Although two recent case reports suggest that superinfection may still occur in chronically infected individuals, either on or off ART,[187,188] the overall conclusion from the literature is that it is extremely rare. Notably, even when superinfection has been found to have occurred, it is only very rarely clinically relevant. Healthcare workers should provide counselling on the possible risks of superinfection and, perhaps more importantly, other STIs for individuals of the same serostatus. The mainly hypothetical risk of superinfection needs to be discussed, taking into account individual circumstances including whether both partners are on suppressive treatment or not. PLHA have to balance the possible risks with other life choices and it is important that discussions occur in an open and supportive environment.

4.6.5 HIV Transmission in HIV Discordant Couples. As mentioned earlier, there is increasing evidence that HAART reduces the risk of sexual transmission and this will play an increasing role in HIV prevention in the future. The fact that almost two thirds of PLHA on HAART in the UK have an undetectable viral load means that information on the risks of HIV transmission on HAART is relevant to many. However, given that the average time for remaining undetectable on ART is limited,[222] there are important considerations that need to be taken into account regarding the public health implications of any recommendations or advice given to patients. Similarly to other national and international positions, the current guideline cannot fully endorse the Swiss consensus statement. However, it is acknowledged that in many instances long-term serodiscordant partners may seek advice about risk reduction in certain instances such as natural conception. Information on risk reduction should be provided because it has been shown that many couples who cannot access fertility services eventually conceive.

4.6.6 Pre-conceptual, Pre-exposure Prophylaxis in Sero-different Couples. The number of centres that provide conception services is limited and in many instances the procedure is costly. Although the exact number of couples who practice unprotected sex in order to conceive is not known, it is likely to be underestimated. It has been reported that up to one-third of couples who have been on waiting lists for fertility clinics do not attend and a significant number of these conceive naturally.[191]

Data on the use of pre-exposure prophylaxis with tenofovir and risk reduction counselling have been presented recently by Vernazza and colleagues.[53] Within counselling discussions on minimizing the transmission risks whilst trying to conceive, 22 couples where the male partner had fully suppressed viral load (<50 copies/mL) were offered the option of timed intercourse with tenofovir pre-exposure prophylaxis. With 50% of women conceiving after three cycles, the conception rate was higher than with artificial conception techniques and all of the women tested negative 3 months after last exposure. These preliminary data and results from pre-exposure animal studies suggest that harm reduction strategies such as this will be important for the future but currently no recommendation on the use of pre-conception prophylaxis for sero-discordant couples can be made.

4.6.7 Key Points and Recommendations.

  • HAART reduces the risk of HIV sexual transmission and for individuals with chronically suppressed viral loads the transmission risk may be negligible in the absence of STIs (II).

  • In most circumstances, counselling and advice should continue to promote the use of condoms to reduce the transmission risk of HIV and other STIs (III).

  • Detailed individual counselling including the use of harm reduction should be available for individuals in sero-different and sero-same long-term relationships who wish to consider unprotected sexual intercourse (IV).

  • The risk of HIV superinfection may diminish with the time from initial infection. Although it appears more likely in the first 3 years following seroconversion, a risk persists after this (II).

  • HIV-positive individuals should be counselled regarding the low but possible risk of superinfection, particularly those who choose to serosort (i.e. have unprotected intercourse with partners who are also HIV-positive) (II).

4.7 HIV, Disclosure and Criminalization

There have been several UK convictions for transmission of HIV from individuals who were aware of their status to other individuals and it is important that healthcare professionals and all those involved in the care of HIV-positive people are aware of the issues regarding this important topic. The situation is complex with several important factors that have relevance, including duty of care, client confidentiality, public health concerns, the doctor-patient relationship and the need for a trusted protective environment in which issues of disclosure can be raised and explored.

No simple guidance can be issued but healthcare workers and services should be aware of the issues and should develop local policies and guidance on partner notification and disclosure. A recent briefing paper is available for review,[224] and further guidance will be made available as it is published. The briefing paper focuses on the responsibilities and duties of healthcare staff, and provides guidance on the duties of healthcare workers regarding confidentiality and disclosure. It is important to stress that although this is not accepted guidance there are some key areas for which there are accepted professional standards.

  • A healthcare worker must properly advise a patient on ways of protecting their sexual partners from infection. A failure to do this may give rise to legal liability if the patient's sexual partner becomes infected as a result. Liability may also arise where a healthcare worker negligently fails to diagnose the patient as having the infection.

  • A healthcare worker has a legal responsibility to maintain confidentiality of patient information unless the patient has consented to disclosure or disclosure is necessary in the public interest. A failure to maintain confidentiality may give rise to legal liability.

  • A healthcare worker may disclose information on a patient (either living or dead) in order to protect another person from serious harm or death. However, there is no statutory obligation to do this.

  • It is also important to remember that disclosure is a process rather than an event and that maintaining trust and therapeutic relationships with patients in order to allow them safe space to examine disclosure issues will ultimately lead to far more beneficial outcomes than threats of litigation.

  • Further useful information on HIV and criminalization is available on the Terence Higgins Trust website (www.tht.org).

4.7.1 Key Points and Recommendations.

  • Healthcare staff should be aware of the important legal issues regarding HIV transmission and their responsibilities to the duty of care of patients, confidentiality and public health concern.

  • All units should develop local policies and guidelines on partner notification and disclosure.

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