D29 Sexually transmitted infections in HIV/AIDS

Introduction

Sexually transmitted infections (STI) can broadly be defined as infections that are transmissible through sexual contacts. Many enteric infections may also be grouped under this category because of their faeco-oral route of transmission sometimes associated with sexual activities, such as viral hepatitis A infection. This is called sexually transmissible enteric infection (STEI) and is discussed towards the end of this chapter. STI is commonly caused by virus including anogenital herpes, anogenital human papilloma virus (HPV) infection and by bacteria including syphilis, gonorrhoea, and Chlamydia trachomatis (serovar L1, 2, 3 that cause lymphogranuloma venereum and B, D to K that cause urethritis and cervicitis). Other common STI agents include Trichomonas vaginalis, and Phthirus pubis.

The World Health Organization (WHO) estimated that more than 1 million STIs are acquired every day worldwide.[1] There are an estimated 375 million new infections of 4 common STIs including chlamydia, gonorrhoea, syphilis and trichomoniasis each year.[1] Over 500 million people are having genital herpes[1] and over 200 million women have human papillomavirus (HPV) infection.[2] In China, despite the stabilisation of the reporting rate of gonorrhoea, syphilis has been on a rising trend in recent years. Notably, men who have sex with men (MSM) gave an estimated prevalence rate of 9.1% for syphilis in a meta-analysis.[3]

In Hong Kong, the Government’s Social Hygiene Service (SHS), the major public service provider for people with STI, recorded about 12,000 new cases of STI and genital tract infections in 2017. The top five STI or reproductive tract infections were, in descending order, non-gonococcal infection and non-specific genital tract infection, anogenital warts, gonorrhoea, syphilis and anogenital herpes. The seroprevalence of syphilis among pregnant women attending local antenatal services was about 0.67% in 2014 [4] and the seroprevalence of herpes simplex 2 virus (HSV 2) was estimated to be about 10%.[5] Despite the decline in overall STI cases in SHS, the number of new cases of syphilis has remained at about 1000 per annum in recent years. The incidence of reported syphilis in MSM was higher in both the setting of SHS and among people living with HIV/AIDS (PLWHA).

Principles of STI management

There are two major approaches in the case management of STI – aetiological and syndromic.[6]

Aetiological approach is the conventional way of managing STI according to the classic microbiological principles i.e. treatment according to the microbe identified by the laboratory. This approach involves attendance at clinic, collection of biologic samples, and their delivery for testing at designated laboratories. In the recent years, a number of new STI diagnostics have been introduced. These include point-of-care tests and tests on self-collected samples. Correct application and proper interpretation of these tests are of utmost importance. There is wide variation of test performance in terms of sensitivity and specificity, and the results could also be operator-dependent. It is important that clinicians requesting these tests familiarise themselves with their performance, and should offer appropriate advice to clients accordingly. The general principles of STI management are in Box 29.1.

Syndromic management is an alternative approach to STI as the aetiological approach may not be always applicable. In resource poor settings, the cost, technological know-how and quality control of concerned STI tests may limit the access to and accuracy of diagnostic tests. In hard-to-reach populations, aetiological approach may not be feasible, even in apparently developed countries. In syndromic case management, people with genital symptomatology and clinical feature are grouped under a few syndromes for which the most likely microbes are considered. Patients are given relevant drug treatment and counselling according to a standard set of algorithms developed in the unique setting of the region. Widely adopted algorithms are those for management of urethral discharge, genital ulcer, and lower abdominal pain syndromes. The World Health Organization (WHO) has developed prototypes of these algorithms (http://apps.who.int/medicinedocs/en/d/Jh2942e/), which could be modified and adapted by individual place. Some of these algorithms are validated in field studies, which are practicable albeit with variable performance. Urethral discharge syndrome algorithm is regarded as the best performed while vaginal discharge algorithm the most variable. The syndromic case management approach has been effective in reducing STI and reproductive tract infections in community based HIV prevention programmes in other countries.

In Hong Kong, an aetiological approach is adopted by SHS for patients who attend the clinics.[HK Guidelines 29A] Management of syphilis and selected STI is discussed in the following sections, while the general approach for all common STI is summarised in Box 29.2.

Syphilis and HIV

In a cross sectional study conducted in an HIV clinic in Hong Kong in 2001, the seroprevalence rate of syphilis among PLWHA was 11%,[7] compared to the general population average of less than 0.5%. Syphilis accounted for almost half of all new cases of STI in a local HIV clinic in 2008. There were reports of the resurgence of syphilis in certain ethnic subgroups in the US. Sero-sorting among HIV positive MSM is suggested to be one of the major reasons for the increase.

Diagnostic procedures for syphilis

Diagnosis of syphilis often poses a challenge to the clinician, beginning with the choice from a myriad of tests available. The following are common ones:

1. Dark ground microscopy
   • Primary syphilis: Spirochaetes can be detected from serum of chancres by dark ground microscopy. To improve the yield, examination for three consecutive days is usually practised in clinics equipped with the technological know-how. The test is less reliable for oral lesion because of the presence of other commensal spirochaetes.
   • Secondary syphilis: Serum from ulcers and condylomata lata can be examined by dark ground microscopy.
2. Skin biopsy
   Although skin biopsy is not the standard investigation of mucocutaneous lesions of primary or secondary syphilis, atypical lesions can be biopsied and examined by Warthin-Starry stain or immunohistochemical study to identify spirochaetes in the histopathological section.
3. Serology
   Serology testing is the mainstay of laboratory testing for syphilis in SHS and other settings in Hong Kong:

   The basic principle is to use a highly sensitive serological test for initial screening, followed by a highly specific test(s) for confirmation. The screening and confirmation test differ in their mechanisms. Serological tests for syphilis are classified into two categories: non-treponemal tests e.g. VDRL and rapid plasma reagin (RPR), and treponemal tests e.g. FTA-ABS, Treponema pallidum haemagglutination assay (TPHA) test, Treponema pallidum particle agglutination test (TPPA), and syphilis enzyme immunoassay (EIA).[8] The testing algorithm of Public Health Laboratory Centre (PHLC), Department of Health is at Algorithm 29A

   Previously, the conventional testing algorithm is used for syphilis testing. It used VDRL and TPHA as a screening test. Once if both were negative, syphilis was screened out. If both were positive, syphilis was affirmed. Whereas, if either one was positive, FTA-ABS would follow for confirming syphilis once the latter tested positive.

   Nowadays, TP EIA is used for syphilis screening. If EIA is positive, quanitative VDRL will then be performed. Once it is positive, syphilis is confirmed. However, if EIA is positive but VDRL is negative, TPPA and FTA-ABS will be performed and syphilis will be affirmed once either TPPA or FTA-ABS is positive. On the other hand if EIA is negative in the initial screening, the Public Health Laboratory will, in accordance with the algorithm, issue report without further serological testing. Nonetheless, if very early syphilis is suspected from clinical assessment, syphilitic serology should be repeated 2-4 weeks later.

   Depending on the serological tests used, syphilis can be confirmed by serology as early as 2 weeks after infection. A second serology test at 3 months is routinely recommended, by then almost all infected cases shall have positive serology.

4. Cerebrospinal fluid (CSF) examination
   Neurosyphilis is characterised by:
   • pleocytosis (lymphocytes >5/μL): pleocytosis can be present in HIV mono-infection, making interpretation of CSF result difficult. An increase of the cut-off to WBC 20/μL is proposed to better indicate true CNS syphilis
   • increased protein >0.4g/L
   • positive CSF VDRL: The problem is that the test is negative in more than a quarter of neurosyphilis cases. Other corresponding syphilis serologic tests, e.g. FTA-ABS on CSF, could be more sensitive but have not yet been standardised, and that they may not be available in the supporting laboratory.

Clinical presentation and treatment

The clinical features and treatment of syphilis are described in Box 29.2. Atypical presentations of syphilis in HIV/AIDS have been well documented. Some examples are: recurrent chancriform ulcer, seronegative secondary syphilis, early and accelerated progression to neurosyphilis, persistent high titred reactive reaginic test after apparently adequate treatment (serofast), relapse after apparently curative treatment, and treatment failure even after high dose intravenous penicillin.

The indication for lumbar puncture (LP) and CSF analysis for HIV infected people presenting with late latent syphilis or syphilis of unknown duration remains the same as those without HIV. LP is also indicated for those having neurologic deficits. All persons with HIV infection and syphilis should have a careful neurologic examination and LP is performed in those with neurologic, ocular and auricular signs and symptoms. CSF leukocytosis is common in HIV patients even without CNS syphilis, thereby a higher cutoff CSF wbc (>20/μL) is used in HIV patients. There are recommendations for HIV-infected patient who has no neurologic deficits but whose CD4 is less than 350 and/or VDRL≥1:32 for LP and CSF analysis at earlier stages of syphilis including secondary and early latent syphilis, which were however not yet supported with good clinical studies. In gist, LP and CSF analysis is recommended for patients who have neurological symptoms/signs or fail to respond to adequate treatment of syphilis. Reactive VDRL-CSF is more specific whereas CSF FTA-ABS is more sensitive with respect to the diagnosis of neurosyphilis, i.e. positive VDRL-CSF in person with clinical suspicion of neurosyphilis confirms and a negative CSF FTA-ABS in an otherwise asymptomatic person should exclude the diagnosis.

The treatment regimens for various stages of syphilis are the same as those non HIV-infected. In practice, penicillin based regimens are strongly recommended. A pivotal study conducted in the US demonstrated that benzathine penicillin in HIV and early syphilis co-infected individuals had a serological relapse rate of 18% at six months. Regular follow-up for relapse is therefore essential. Weekly benzathine penicillin is now adopted by SHS as the standard of care following withdrawal of procaine penicillin from the local market. As benzathine penicillin delivers a low albeit prolonged blood level of active drug that may not amount to a meaningful level in CSF, there is a theoretical risk of untreated CNS disease.

Other STI in HIV infection

Both ulcerative and non-ulcerative STI facilitate HIV transmission by a factor of 2-5 times, more for ulcerative compared to non-ulcerative ones. In Hong Kong, a cross sectional study conducted in 2005 and again in 2008 revealed that 5.1% and 3.4% of the sexually active people attending an HIV clinic had either gonococcus or Chlamydia trachomatis infection from urine PCR screening.[9] These observations highlight the importance of STI screening, diagnosis and treatment for HIV-infected people.

The clinical presentations, natural course and management of STI in people with HIV are usually the same as those non HIV-infected people. However atypical presentations and interactions of significant clinical or public health interest have been extensively reported in the literature. This section provides an overview of selected STI commonly presenting in association with HIV.

Gonorrhoea, Chlamydia, Mycoplasma, Trichomonas and Phthirus pubis

The clinical features and management are described in Box 29.2

Anogenital herpes

There is increased genital shedding of HIV and herpes simplex virus type 2 (HSV-2) in women co-infected with both viruses Moreover, women with HIV are more likely to have higher HIV RNA copy number in their blood. Atypical presentations such as large atypical anogenital ulcer recalcitrant to conventional treatment and hyperplastic or nodular growth have also been reported.

In persons with HIV, the recommended regimens for daily suppressive therapy are: acyclovir 400 – 800mg orally twice to three times a day or famciclovir 500 mg orally twice a day, or valaciclovir 500 mg orally twice a day. The recommended regimens for episodic treatment are: acyclovir 400 mg orally three times a day for 5-10 days or famciclovir 500 mg orally twice a day for 5-10 days, or valaciclovir 1 gm orally twice a day for 5-10 days. The dosages are higher than those in persons without HIV infection.

HPV related infection

People infected with HIV are more likely to have detectable human papillomavirus (HPV) infection regardless of the subtype. Moreover, they stand a higher chance of persistent infection with high-risk HPV types (HR-HPV). Women with HIV are prone to develop cellular atypia in their cervical screening samples, but the degree to which immunosuppression affects atypia is not yet well defined.

Anogenital wart is not uncommon among MSM. There were reports of increased risk of anal carcinoma among MSM with HIV infection. Although screening for anal carcinoma in HIV infected MSM has been adopted in some centres in US and Australia, there is not yet a standard recommendation on anal intraepithelial neoplasia screening and management. The risk for abnormal anal “Pap smear” is better associated with anal sex and man-to-man sex than level of immunosuppression defined by CDC class or CD4 count. Atypical presentations such as extensive growth, recalcitrant to treatment, accelerated progression to high grade lesions, and cervical cancer or anal cancer after infection with HR-HPV, have been were reported. An increase in incidence of oral warts has been described as a manifestation of immune reconstitution syndrome in people with HIV receiving HAART.[Chapter C17]

Sexually transmissible enteric infection (STEI) and viral hepatitis

Previously referred as ‘Gay bowel syndrome’, sexual transmission of STEIs may occur in sexually active MSM as a result of direct or indirect oral-anal contacts.[10] This is a broad group of infections which could occur in sexually active PLWHA, the commoner pathogens being Shigella spp., Entamoeba histolytica, Campylobacter spp., and hepatitis A. Less common causes are Giardia lamblia, Salmonella spp. and E. coli. Outbreaks of STEI have been reported in UK , Spain, Canada, Taiwan and also internationally. An outbreak of hepatitis A involving 43 cases with 76.7% of which HIV positive occurred in 2016/2017 in Hong Kong.[11]

Hepatitis B virus (HBV) can be sexually acquired. Since the implementation of universal childhood vaccination against HBV in the 1980s, a majority of young people born in Hong Kong are protected from HBV infection. Nevertheless a higher proportion of HIV positive individuals are tested positive for HBV markers. For hepatitis C virus (HCV), sexual transmission is not known to be an important mode of spread. In the past decade, however, an increasing number of HCV infections have been reported in MSM in different countries, especially among those living with HIV/AIDS.[12] In Asia and the Pacific, HCV outbreaks linked with sexual exposure have been reported in Taiwan, Japan and Hong Kong. Some of the infections might be associated with chemsex and related increase in high risk sexual behaviours.

Screening for STI in HIV infection

Some people living with HIV remain active sexually and hence are vulnerable to STI if safer sex practice is not consistently adopted. Recommendations on STI screening are developed in the US and UK with the objective of improving sexual health. The Melbourne Sexual Health Centre recommends serological screening for all MSM with HIV whenever they have blood testing for other purposes.[13] Such strategy carries also public health implication in enabling early detection of STI which could be followed by not just treatment but appropriate behavioural interventions. In the process of implementing these recommendations, there should be parallel development in such areas as sexual health risk assessment and counselling, clinical and laboratory management of the implicating STI, partner management, and the maintenance of sexual health referral network.

In practice, screening strategies vary from one setting to another. For sexually active PLWHA, baseline STI screening for syphilis, gonorrhea and chlamydia is recommended, followed by annual or more frequent screening depending on individual risk behaviours.[14] Algorithm 29B shows a protocol for use in HIV specialist clinic or primary care services.

Further tests for other STI or the collection of clinical samples from sites other than those specified in the algoritghm are indicated, which should be guided by results of clinical assessments. More frequent STI screening may be appropriate depending on individual risk behaviour, local STI epidemiology especially in an outbreak situation. The protocol is not meant to replace routine clinical management of people with symptomatology or clinical features suggestive of STI.

Reference:

Hong Kong Guidelines