Viral Sexually Transmitted Infections

Unlike bacteria, viruses are non-living particles which require a living host cell's machinery to replicate. They have small DNA or RNA genomes enclosed within a protein capsid (protective coat)[1]. Depending upon the lifecycle of the virus and method of replication, infections may either be acute (short-term as seen in the common cold), latent (cycles of infection as explained in Herpes) or chronic progressive (slow, insidious infection with a long incubation period and often very severe/fatal effects, as seen in HIV)[1].

Herpes
Herpes, as caused by the large enveloped Herpes Simplex Virus, refers to the large, swollen infectious blisters (which later burst to become crusty brown sores)[1,2]. These can be found on either the mouth (cold sores usually result from HSV-1) or the genitals (genital herpes usually result from HSV-2), and typically results from skin-to-skin contact with one of the sores, particularly during sex (including oral sex)[1,2]. After successfully 'defeating' the active infection (associated with disappearance of the sores), it hides in a dormant/latent state in the dorsal root ganglion of the nerve associated with that region of skin, only to reactivate in periods of immune suppression (usually stress, extended UV exposure, chemotherapy or AIDS)[1,2].

While transmission is common during active infection (with sores visible), transmission during latency is rare (but has been recorded)[2]. Approximately 15-20% of individuals in the 15-49 age bracket are estimated to be living with HSV-2 infection, and this number is much greater for HSV-1[3].

Other forms of infection include;

• Infection of unusual sites, such as the conjunctiva of the eyes (leading to keratoconjuctivitis), hands, breasts, buttocks, lower back and fingers (herpetic whitlows are painful digit lesions)[1,2]. For infection of these sites, invisible tears of the skin must have been present for the virus to penetrate.
• Herpes Simplex Encephalitis (HSE is extremely rare) occurs when 'retreating' viral particles enter the brain via the trigeminal nerve (associated with cold sores), where it promotes inflammation and swelling of the brain, often leading to severe confusion and rapid death[1].
• Neonatal Herpes occurs when the child (during childbirth) comes into contact with infective lesions of the mother. Congenital herpes is one of the most life-threatening infections in neonates as it regularly produces blindness and neurological deficits in the neonate (all active pregnant mothers should have a caesarian section performed)[1,2].

Diagnosis involves taking a swab of one of the lesion and laboratory analysis (results are most reliable if taken within four days of developing the sore)[2]. While there is no cure for Herpes, the use of paracetamol/other painkillers/anaesthetic jelly for the pain, antiseptic/salt solutions to prevent secondary bacterial infection of the sore and antiviral medications (particularly if recurrent episodes are frequent) may reduce the symptoms and morbidity associated with life-long infection[2]. Sexual activity should be avoided if either you or your partner exhibit any signs of active infection.

HIV

The earliest case of Human Immunodeficiency Virus (HIV) in humans was actually reported in 1959, although the subsequent Acquired Immune Deficiency Syndrome (AIDS) was only seen in 1981 (in five otherwise-healthy homosexual young American men)[1,4]. Isolation of the virus in 1983 allowed the development of government recommendations to prevent transmission and vaccination research programs; efforts are hindered due to rapid adaption and incredible diversity throughout the four genetically-distinct groups (HIV-1 M, HIV-1 O, HIV-1 N and HIV-2)[1]. Modes of transmission include blood contact (intravenous drug use, blood transfusions, in-surgery exposure and needlestick accidents), sexual (oral, vaginal and anal sex) and from infected pregnant mother to child, and this is promoted by the presence of genital lesions (particularly co-infection with syphilis and herpes)[5].

HIV is now a worldwide pandemic, with ≈2.3 million new cases (≈1.6 million or ≈70% in Sub-Saharan Africa), ≈1.6 million deaths (≈1.2 million or ≈75% in Sub-Saharan Africa) and ≈35 million infected globally (≈25 million, or ≈71% in Sub-Saharan Africa) every year; in countries such as Botswana, Lesotho and Swaziland over 20% of adults are infected[4]. Of all the adults living with HIV, ≈60% of the females and ≈40% of the males are aged 15-24[4]. In Western Australia, this number is much lower, with ≈120 notifications per year, with a 4:1 ratio of males:females and no Aboriginal cases[6]. Half of all Western Australian infections were in homosexual males[6].

Primary infection with HIV is characterised by glandular fever/flu-like illness with malaise, joint and muscle pains, swollen lymph nodes and rash in >70% of infected individuals (with a window period, where infection cannot be identified, of 5.3 days)[1,4]. After only 2-6 weeks, the infection continues without symptoms for ≈10 years without treatment (although the individual is sill infectious)[1]. The emergence of symptoms such as fevers, night sweats, diarrhoea, weight loss, thrush, Kaposi’s sarcoma (a type of endothelial cancer), leukaemias, shingles (requires previous chickenpox infection), herpes reactivation, pneumonia, confusion and other symptoms of serious opportunistic infections are indicative of immune suppression associated with AIDS[1,6]. The eventual loss of immunity leads to the infection of the respiratory, gastrointestinal and nervous systems which leads to disability, a loss of livelihood and death[1,5].

Detection involves a simple blood test and laboratory analysis; this can further determine both the viral load and the concentration of the affected CD4⁺ T-helper cell population (these indicate not only the presence of infection but can monitor the rate of disease progression)[1,4]. This disease progression is significantly affected by host factors (receptor mutations such as CCR5Δ32, and hereditary immune system variability such as B27, B57 or B35 haplotypes), viral factors (relative competence) and co-infection with certain disease (particularly Tuberculosis and Hepatitis C)[4,7].

While no cure for HIV exists, treatment acts to reduce disease progression and symptoms, and takes the form of Highly-Active AntiRetroviral Treatment (HAART)[1,4,7]. HAART uses a variety of drugs which prevent various stages of the viral replication cycle, ranging from preventing entry (Entry and Fusion Inhibitors) to interfering with the insertion of the viral genome into the host genome (Reverse Transcriptase and Integrase Inhibitors) and finally to inhibiting the formation of functional proteins and hence viral particles (Protease Inhibitors)[1,4]. Unfortunately the development of drug-resistance mutations throughout the course of treatment often results in the eventual ineffectiveness of current therapy; thus drugs can be expected to only last a maximum of 30-40 years even if stringently adhered to[1,7].

Hepatitis B

The Hepatitis B Virus (HBV) is commonly transmitted from one person to another via infected blood (needle sharing, tattooing, renal dialysis, organ transplantation and blood transfusion) or other body fluids (saliva, sweat, semen, vaginal fluid, breast milk, urine, faeces), thereby allowing spread during sexual intercourse and during pregnancy, birth and breast-feeding (from mother to child)[1]. Interestingly, infection can occur following simple close contact (saliva and sweat are common in environments such as classrooms, prisons and families; this mode of transmission is relatively small)[1]. High-risk groups (without consideration of vaccination) include injecting drug users, health-care workers, homosexual men, the sexually promiscuous, prisoners, immigrants from endemic regions/travellers, dialysis/blood transfusion recipients (where screening is poor) and indigenous populations[8].

HBV is considered endemic to a region if the prevalence is more than 5%, and is seen in the North American Tundra, Amazon, Eastern Europe and Mediterranean, South-East Asia, East-Asia and the Pacific Basin (except New Zealand and Japan)[8,9]. More than 2 billion people are infected worldwide, 350 million live with chronic infection and approximately 1 million deaths occur every year[9]. In Western Australia, there are ≈600 notifiable infections every year, ≈40 of which are new cases[6].

While most acute cases are asymptomatic (only 1% of neonates, 10% of children aged 1-5 and 30% of older individuals show acute symptoms), these occur 1-3 months after exposure[7,8] Common signs and symptoms include fever, extreme tiredness (often for weeks or months), a loss of appetite, nausea, vomiting, joint and muscle pain, and yellowing of the eyes and skin (jaundice results from damage to the liver during viral replication)[1,8,9]. Only 1% of chronically-infected individuals experience the catastrophic and rapid liver damage (70% mortality) associated with fulminant hepatitis[8].

Clearance of the acute infection is highest in those with functional immune systems and typically occurs within six months; 80-90% of neonates, 30% of young children aged 1-5 and 5% of healthy adults later develop chronic infection[8,9]. Chronic infection and resulting inflammation lead to either progressive liver damage (cirrhosis leading to liver failure in 20%) or liver cancer (HBV-related hepatocellular carcinoma is responsible for 80% of liver cancers and occurs in 5% of those with chronic infection)[1,8,9]. Factors promoting disease progression include concurrent HIV infection, alcoholism or excessive alcohol use, drug use (some drugs are toxic to the liver) and exposure to other environmental toxins[1,8].

Since the development of the recombinant HBV vaccine in 1982 (more than 95% effective), 92% of UN Member states have initiated vaccination programs (with only 48% provide neonatal vaccinations)[9]. As immunity declines steadily during mid-life, revaccination is effective, and in the case of accidental exposure, an 'antidote' is available (must be administered within 48 hours)[1,8].

Diagnosis requires a simple blood test and laboratory analysis, and the presence of specific markers can determine the type of infection (acute, chronic persistent or chronic active)[1,8]. Treatment for acute or chronic infection involves the use of antivirals such as adefovir, dipivoxil and lamivudine[1].If an individual knows they are infected, they need to be extremely vigilant regarding cleanliness to prevent exposure to others (always use sexual protection, do not share needles, advise appropriate health professionals, cover wounds, clean up bodily fluid spills and don't share toothbrushes or drink containers), as the HBV can remain infectious up to 7 days outside of humans[8].

Hepatitis D refers to 8 related 'strains' of small virus-like particles which require concurrent HBV infection for transmission (therefore distribution is limited to endemic HBV regions[1,8]. When an individual contracts both HBV and HDV simultaneously, it produces a characteristic severe acute disease with a low risk of chronic infection[1]. In contrast, superinfection (when an HBV carrier is later infected with HDV) produces acute hepatitis and almost always leads to the development of cirrhosis and liver failure over 10-20 years[1,8].

Hepatitis C

The Hepatitis C Virus (HCV), unlike HBV, is transmitted from one person to another via infected blood (not through saliva, sweat, urine and faeces and rarely through sexual fluids such as semen or vaginal secretions)[10,11]. As a result, typical infection occurs during needle-sharing, accidental needlestick injury, tattooing/piercings, sexual activity (only if damage to the soft mucosal lining and blood contact occurs), sharing infected personal items (razors, toothbrushes, etc) and during birth (viral particles can infect the neonate during delivery with a 5% transmission rate)[11].

WHO estimates that ≈3% of the world's population are infected, with 150-170 million people currently living with symptomatic HCV infection; this number is remains relatively constant despite 3-4 million new (acute) cases and 350,000 deaths each year[11]. 'Strains' 1a and 1b are responsible for ≈60% of global infection (predominate in Westernised countries)[10]. Groups with particularly high infection risk include intravenous drug users, sex workers (from drug use), health-care workers, recipients of poorly-screened blood/organ transplants (including haemophiliacs), tattoo artists (and their consumers) and children born to infected mothers[10,11]. Worldwide epidemiological data is scarce and unreliable[1,10,11], although in Western Australia there are ≈1100 cases every year, ≈125 of which are newly-acquired; males have twice the prevalence than females, and Aboriginals have a seven-fold higher rate[6].

After an incubation period of 6-10 weeks, acute infection produces a milder form of hepatitis than HBV (symptoms such as weight loss, vague stomach discomfort, nausea and vomiting, fever, tiredness and jaundice occur in only 20-25% of infected individuals)[1,10,11]. While ≈20% clear the virus following acute infection, ≈15% become lifelong (infectious yet asymptomatic) carriers and the remaining ≈65% experience progressive liver disease up to 20-30 years after exposure[1,10,11]. Approximately 20% of those suffering chronic liver disease (a result of excessive inflammation in response to viral infection) will develop cirrhosis (≈¼ then develop hepatocellular carcinoma each year, with another ¼ experiencing liver failure per annum)[1,11]. Fulminant hepatitis is extremely rare in HCV[10]. Factors affecting HCV disease progression include concurrent HBV and HIV infection, alcohol use and abuse (threefold risk increase with alcoholism), fatty liver, HCV strain virulence, drug use and exposure to other environmental toxins[10]. In developed countries, HCV-related liver failure is the primary cause for liver transplant (70% 5-year survival rate in Europe)[1,10]

Detection involves a simple blood test and laboratory analysis[10]. No vaccine currently exists for HCV as the high genetic variability of the virus makes it difficult to target. Current treatment involves combined antiviral treatment with pIFNα and ribavarin. which c This clears the virus in 45-80% of chronic carriers (factors include ethnicity, host immune factors, concurrent HIV infection and the type of HCV[1].  A patient is cured when they show no detectable virus in blood 6-12 months after stopping antiviral therapy.

Genital Warts

Warts (also called verrucae) are small raised lumps of the skin resulting from one of the many Human Papillomaviruses (HPVs).With more than 100 strains, they vary in their preferred site of infection (ranging from skin to the soft mucosal linings), their symptoms and signs and (in some select strains) their ability to cause cancers[1]. The four main types of warts are plantar warts, verrucae vulgaris, flat warts and venereal warts (strains which produce the latter type are considered STIs)[1].

More than half of all sexually-active individuals are infected with at least one strain of HPV in their lifetime, with half of all cases occurring in sexually-active youths in the 15-24 age bracket[1]. Major risk factors include early age of first sexual contact, promiscuity and promiscuity of sexual partners and immunosuppression (ultimately infection with HPV). Minor risk factors include the use of oral contraceptives, smoking, number of children, family history, coinfection with other STIs and lack of circumcision in male partner[1,12]. With an incubation time of 1-6 months, the vast majority of HPV infections have no adverse effects and are eventually cleared by the immune system (90% within 2 years); strains 6 and 11 are responsible for ≈90% of genital warts[1,12,13].

However, HPV is also responsible for more than 99% of all cervical cancers, with ≈70% resulting from the high-risk strains 16 and 18[1]. More than half a million women develop cervical cancer every year, and ≈90% of the ≈300,000 deaths each year occur in developing countries. Cervical cancer results from the insertion of viral oncogenes into host cervical cells, promoting uncontrolled cell growth and development of precursor lesions. While the vast majority may remain benign for 10-20 years, some may become invasive and malignant, producing cervical cancer[12]. In a similar way, HPV-16 and HPV-18 are also the leading causes of anal (90%), oropharyngeal (>12%) and vulval, penile and vaginal cancers (40%)[12].

Signs and symptoms of cervical cancer include the presence of visible white tumours (in colposcopic examination), bleeding after sexual intercourse, bleeding between periods, unusual vaginal discharge and ulceration and pain (particularly during/after sexual activity)[12].

The quadrivalent HPV vaccine (protects against types 6, 11, 16 and 18 with almost >95% success after five years with no serious side effects) has seen a significant decrease in the rate of infection and cervical cancer development[1,13]. This vaccine is currently recommended for all school-age children, and takes the form of three upper-arm injections over a six-month period[13].

Pap smears (cytological analysis) are still the most effective population-scale screening method to detect precursor lesions if performed properly (well-trained personnel using quality equipment) every three years in those 25-50, (and every five years in those 50-65 years of age)[12]. Colposcopy and tissue sampling is then recommended in the case of positive Pap smear results for a reliable diagnosis (and then should only be performed by trained and skilled professionals)[12].

Removal of small, simple precursor lesions typically uses cryotherapy or loop electrosurgical excision procedure, although these are ineffective with invasive tumours and cannot be performed if the woman is pregnant or has an active cervical infection (or PID)[12]. Cryotherapy uses a supercooled metal disk to freeze-burn the mass with ≈90% success, while LEEP uses a superheated thin wire to cut out and seal the tissue mass with ≈95% success[12]. For mid-stage cervical cancers, surgical excision of the infected region (cold knife conisation) is recommended (90-95% success rate), although this requires hospitalisation and anaesthesia, and cannot be performed if the woman is pregnant (damage to the cervix may also lead to infertility) or has PID[12].

For large or metastatic end-stage cancers both removal of the primary tumour, surrounding tissue (often requiring removal of the cervix aka. trachelectomy, womb aka. hysterectomy and sometimes in advanced cases removal of surrounding infected immune tissue aka. lymphadenectomy by trained gynaecological surgeons) and radio/chemotherapy is essential[12].

References

1. Willey JM, Sherwood LM, Woolverton CJ. Prescott's Microbiology. 8th ed. Singapore: McGraw-Hill; 2011.
2. Department of Health (WA). Genital Herpes Fact Sheet [Internet]. Perth, WA (Australia): Department of Health (WA); 2012 [cited 2014 Mar 29]. Available from: http://www.public.health.wa.gov.au/2/408/2/genital_herpes_fact_sheet.pm. 
3. Looker KJ, Garnett GP, Schmid GP. An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. Bull World Health Organ. 2008 Oct;86(10):805-12.
4. UNAIDS. UNAIDS report on the global AIDS epidemic 2013. Geneva: UNAIDS; 2013. Available from: http://www.unaids.org/en/resources/campaigns/globalreport2013/globalreport/.
5. World Health Organization. Global incidence and prevalence of selected curable sexually transmitted infections – 2008. Geneva: World Health Organization, Department of Reproductive Health and Research; 2012. Available from: http://www.who.int/reproductivehealth/publications/rtis/stisestimates/en/index.html.
6. Department of Health (WA). Quarterly Surveillance Report: Notifiable Sexually Transmissible Infections and Blood-borne Viruses in Western Australia - December 2013 [Internet]. Department of Health (WA) - Public Health and Clinical Services; 2014 Feb [cited 2014 Mar 26]. Report No.: 11(1). Available from: http://www.public.health.wa.gov.au/cproot/5693/3/stibbv_2013_4th_quarterly_report.doc.
7. Poropatich K, Sullivan DJ Jr. Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression. J Gen Virol. 2011 Feb;92(Pt 2):247-68.
8. World Health Organization. Hepatitis B. Geneva: World Health Organization, Global Alert and Response Group; 2002 Available from: http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/.
9. World Health Organization. Hepatitis B Fact Sheet [Internet]. Geneva (Switzerland): World Health Organization, Global Alert and Response Group; 2013 [cited 2014 Mar 30]. Available from: http://www.who.int/mediacentre/factsheets/fs204/en/.
10. World Health Organization. Hepatitis C. Geneva: World Health Organization, Global Alert and Response Group; 2003 Available from: http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/.
11. World Health Organization. Hepatitis C Fact Sheet [Internet]. Geneva (Switzerland): World Health Organization, Global Alert and Response Group; 2013 [cited 2014 Mar 30]. Available from: http://www.who.int/mediacentre/factsheets/fs164/en/.
12. World Health Organization. Cervical cancer, human papillomavirus (HPV), and HPV vaccines - key points for policy-makers and health professionals. Geneva: World Health Organization; 2008. Available from: http://www.who.int/reproductivehealth/publications/cancers/RHR_08_14/en/.
13. World Health Organization. Comprehensive cervical cancer control: a guide to essential practice. Geneva: World Health Organization; 2006. Available from: http://whqlibdoc​.who​.int/publications/2006/9241547006_eng​.pdf.