12

Sexually transmitted infections and human immunodeficiency virus

Janet D Wilson, Jane Anderson

Sexually Transmitted Infections

Sexually transmitted infections (STIs) are among the most common causes of illness in the world and remain endemic in all societies. They have a profound impact on sexual and reproductive health, and rank among the top five disease categories for which adults seek healthcare worldwide.

The World Health Organization (WHO) estimated that in 2008 there were over 498 million new cases of the four major curable STIs in adults aged 15–49 throughout the world. These included 10.6 million cases of syphilis, 106.1 million of gonorrhoea, 105.7 million of chlamydia and 276.4 million of trichomoniasis. The estimates suggest that the vast majority of these infections were in low-income countries. The pattern of STIs is usually different in high-income countries: for example, in England in 2013, the most common STIs were chlamydia (208 755; 47%), genital warts (73 418; 17%), genital herpes (32 279; 7%) and gonorrhoea (29 291; 7%). The public health, social and economic consequences of STIs are extensive, both for acute infections and for their longer-term sequelae. The inflammation caused by one STI can increase the risk of acquisition of others, and most infections increase the acquisition and transmission of the human immunodeficiency virus (HIV).

The highest prevalence of STIs is in young people, men having sex with men (MSM) and bisexual men, and black and ethnic minority populations. STIs are associated with high-risk sexual behaviour, more frequent partner change and inconsistent use of condoms. Increased travel, both within and between countries, recreational drug use and alcohol are also implicated.

All STIs can be asymptomatic and multiple infections frequently coexist; hence many people without symptoms attend sexual health clinics to seek sexual health checks and advice.

Clinical Approach to the Patient with an STI

Patients presenting with possible STIs are frequently anxious, embarrassed and concerned about confidentiality. Staff must be alert to these issues and respond sensitively. The clinical setting must ensure privacy and reinforce confidentiality.

History

The history of the presenting complaint usually focuses on genital symptoms, the most common being:

• urethral discharge in males (Box 12.1)

• vaginal discharge (Box 12.2)

• lower abdominal pain (Box 12.3) in females

• genital lumps (Box 12.4)

• genital ulceration (Box 12.5)

image Box 12.5

Causes of genital ulceration

• genital itching (Box 12.6)

• rectal symptoms (Box 12.7).

image Box 12.7

Causes of rectal symptoms

• Symptoms of proctitis are rectal pain, mucopurulent anal discharge, rectal bleeding, constipation and tenesmus

• Proctoscopy may reveal mucosal erythema, oedema, contact bleeding and a mucopurulent discharge, with ulceration in severe cases

Details should be obtained of any associated pain, malodour, genital swelling and any abnormal bleeding. Systemic symptoms of fever, skin rash, joint pains and eye symptoms may also be present. Enquiries should be made as to any previous STIs, including dates and treatment received, HIV testing and results, and hepatitis B vaccination status if appropriate (see pp. 320–321).

A full general medical history should be obtained, including a history of allergies and a drug history, particularly of any recent antibacterial or antiviral treatment. In women, a menstrual, obstetric and cervical cytology screening history should be obtained, as well as details of current contraception. Any past or current history of drug (including recreational use) and/or alcohol misuse should be explored.

A sexual history should be taken that includes:

An STI and HIV acquisition risk assessment should be routinely undertaken. Those identified as being at high risk of STIs (e.g. frequent partner change, unprotected sex, use of drugs and/or alcohol to a level that reduces safer sex) and those with ongoing higher risk of HIV (e.g. MSM, sexual partners from countries with high HIV prevalence) should be offered risk reduction advice based on motivational interview techniques and be made aware of the availability of post-exposure HIV prophylaxis following sexual exposure (PEPSE). See page 347 for more details.

Examination

The inguinal, genital and perianal areas should be examined using a good light source. The groins should be palpated for lymphadenopathy, and the pubic hair and skin examined for nits and lice and any skin rashes or lumps. The external genitalia and perianal area should be examined for signs of erythema, fissures, lumps, ulcers, pigmented or hypopigmented areas. A rectal examination/proctoscopy should be performed in patients with rectal symptoms, in those with perianal warts extending into the anal canal, and in men with prostatic symptoms.

In men, the skin of the penile shaft (retracting the prepuce if present) should be examined for rashes, lumps, or ulcers, and the urethral meatus should be inspected for erythema and discharge (Fig. 12.1). The scrotal contents should be palpated, noting any tenderness or lumps, as well as the consistency of the testes.

image
Figure 12.1 Mucopurulent urethral discharge.

In women, the labia majora, labia minora, clitoris, urethra, introitus and perineum should be examined for rashes, lumps or ulcers. Any evidence of female genital mutilation (FGM) should be documented. A bivalve vaginal speculum should be inserted and the vagina examined for erythema, discharge, lumps or ulcers. The cervix should be inspected and any ectopy noted, as well as any discharge (Fig. 12.2A), contact bleeding (Fig. 12.2B), ulceration or raised lesions. A bimanual pelvic examination should be performed in those complaining of abdominal pain to determine the size and any tenderness of the uterus, as well as any cervical motion or adnexal tenderness and the presence of any masses.

image
Figure 12.2 Cervicitis. A. Purulent discharge. B. Contact bleeding.

If systemic symptoms have been identified, a general examination should be performed with inspection of the skin, mouth, pharynx and lymph nodes. Signs of HIV infection are covered on p. 336.

Investigation of STIs

Although the history and examination will guide investigations, it should be remembered that multiple infections may coexist and may be asymptomatic. Tests for all STIs are indicated in any patient with a known STI or in those who have been in contact with an STI. The recommended tests for specific infections are indicated in the sections below.

Asymptomatic STI screening

The minimum investigations should include tests for chlamydia, gonorrhoea, syphilis and HIV. HIV antibody testing should be performed on an ‘opt out’ basis. If it is declined, the reasons why should be documented. Screening for hepatitis viruses should be performed in those at increased risk, as indicated below.

Screening for hepatitis A and vaccination. Test for antibodies to hepatitis A (with vaccination if negative) should be performed in injecting drug users, people with chronic hepatitis B or C, or HIV, and MSM in areas where an outbreak of hepatitis A has been reported.

Screening for hepatitis B and vaccination. The recommended screening test in those who have not been immunized is immunoglobulin G (IgG) anti-hepatitis B core (anti-HBc), which is a marker of past infection. If positive, hepatitis B surface antigen (HBsAg) testing should be performed, as this identifies currently infected individuals. Screening is recommended for the following: sexual partners of those who are HBsAg-positive, MSM and their sexual partners, people who have been sexually assaulted, sex workers, injecting drug users and their sexual partners, individuals or those with a sexual partner from countries with a high prevalence of hepatitis B (which are countries outside Western Europe, North America and Australasia), needle-stick recipients, people with chronic hepatitis C or HIV, and those born to a mother infected with hepatitis B. Patients who are negative and have ongoing increased risk should be offered vaccination.

Screening for hepatitis C (HCV). Screening for antibodies to hepatitis C is recommended in the sexual partners of HCV-positive people, injecting drug users, needle-stick recipients, people with chronic hepatitis B or HIV, and those born to a mother infected with HCV.

Investigations for symptomatic patients

The investigations will depend on the clinical presentation but should always include tests for chlamydia, gonorrhoea, syphilis and HIV. The recommended investigations for these presentations are shown in Boxes 12.1–12.7.

Management, prevention and control

The treatment of specific conditions is covered in the appropriate sections. Most sexual health clinics give directly observed therapy where possible or dispense medication directly to the patient to improve adherence in order to prevent onward transmission.

Tracing the sexual partners of patients is crucial in controlling the spread of STIs. The aims are to identify and treat those with infections (particularly those with asymptomatic infections) in order to prevent the spread within the community. Also, appropriate antibiotic therapy is usually offered to recent sexual partners of those known to have an active infection (epidemiological treatment). Interviewing people about their sexual partners requires considerable tact and sensitivity, and specialist health advisers are available in sexual health clinics.

Many STI diagnoses are in young adults (16–24 years). Prevention starts with education and information. People begin sexual activity at ever-younger ages and education programmes need to include school pupils, as well as young adults. Education of health professionals is also crucial. Primary public health prevention aimed at informing groups at particular risk in order to modify sexual behaviour should be implemented at a national level. Secondary interventions include the prompt diagnosis and appropriate management of STIs in order to reduce complications and onward transmission. The National Chlamydia Screening Programme (NCSP) in England aims to provide earlier detection and treatment for chlamydia by providing easy access for under-25-year-olds to chlamydia testing in community settings.

Reducing the numbers of sexual partners, avoiding overlapping relationships, using condoms correctly and consistently, and avoiding sex if symptoms are present can reduce the risks of acquiring and transmitting an STI. For those who change their sexual partners frequently, regular check-ups (approximately 3-monthly) are advisable. Once people develop symptoms, they should be encouraged to seek medical advice as soon as possible to reduce complications and spread to others.

Further reading

British Association for Sexual Health and HIV (BASHH). BASHH Clinical Effectiveness Guidelines. BASHH; available online at http://www.bashh.org/.

Mercer CH, Tanton C, Prah P et al. Changes in sexual attitudes and lifestyles in Britain through the life course and over time: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet 2013; 382:1781–1794.

Sonnenberg P, Clifton S, Beddows S et al. Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet 2013; 382:1795–1806.

Winter A, Ross J (eds). Sexually transmitted infections – Parts 1 and 2. Medicine 2014; 42:281–404.

World Health Organization. Global Incidence and Prevalence of Selected Curable Sexually Transmitted Infections – 2008. Geneva: WHO; 2012.

Specific Infections

image HIV/AIDS

This is discussed on pages 331–355.

image Hepatitis B

This is discussed on pages 454-457. Sexual contacts should be screened and immunized if they are not immune.

image Chlamydia trachomatis

C. trachomatis (CT) is the most common STI in the UK; up to 10% of sexually active people below the age of 25 years are infected. It infects the urethra, endocervix, rectum, pharynx and conjunctiva, and is transmitted by direct inoculation of infected secretions from one mucous membrane to another. As up to 80% of women and 50% of men may be asymptomatic, it is frequently unrecognized and therefore untreated. Pelvic inflammatory disease, the main complication of CT, can result in tubal infertility, ectopic pregnancy and chronic pelvic pain, causing significant morbidity and cost to health services.

image Clinical features

The exact incubation period is unclear but is thought to be between 7 and 21 days.

In men, it can cause an anterior urethritis with a mucoid or mucopurulent urethral discharge (which may be worse on waking, when there may be crusting at the meatus) and dysuria. The infection can ascend along the vas deferens, leading to epididymo-orchitis.

In women, the most common site of infection is the endocervix but the urethra can also be infected. Symptoms may include increased vaginal discharge, dysuria, postcoital or intermenstrual bleeding, and lower abdominal pain. Examination of the cervix may reveal mucopurulent cervicitis and/or contact bleeding. Ascending infection into the uterus and fallopian tubes causes endometritis and acute salpingitis (pelvic inflammatory disease). In pregnancy, CT is associated with preterm birth, postpartum infection, and neonatal mucopurulent conjunctivitis and pneumonia due to vertical transmission during vaginal delivery.

Rectal infection, through receptive anal sex, may be asymptomatic but can cause proctitis. Reactive arthritis (see p. 686) can occur with CT infection, particularly in human leucocyte antigen (HLA)-B27-positive individuals.

image Diagnosis

Nucleic acid amplification tests (NAATs) are the diagnostic tests of choice for CT, as they have sensitivities of 90–99%. In men, first-voided urine (FVU) samples or urethral swabs, and in women vulvo­vaginal swabs (VVSs) or endocervical swabs, are taken. Self-taken VVSs are as sensitive at detecting CT as clinician-taken VVSs but FVU samples in women are less sensitive than VVSs and endocervical swabs. The advantages of male FVU samples and self-taken VVSs is that they are non-invasive (meaning they can be obtained by the patient without the need for an examination), so are ideal for asymptomatic chlamydia screening.

MSM who practise receptive anal sex and receptive oral sex should have rectal and pharyngeal swabs for CT NAAT performed.

image Management

Macrolide or tetracycline antibiotics are most commonly used to treat CT. Azithromycin 1 g as a single dose or doxycycline 100 mg ×2 daily for 7 days is the recommended regimen for uncomplicated infection. Both of these drugs have similar efficacies of more than 95%. Azithromycin 1 g as a single dose is recommended in pregnant or lactating women by WHO, USA, UK and Australian guidelines but the manufacturers advise use only if adequate alternatives are not available. Tetracyclines are contraindicated in pregnancy. Longer courses of antibiotics are required for complicated infections (see pelvic inflammatory disease and epididymo-orchitis below). Epidemiological treatment pending test results is usually offered to those who have had recent sexual intercourse with someone who has confirmed CT infection, as the infection rate can be up to 50%. Abstinence from sex for at least 7 days, or until treatment is completed, should be advised. Sexual contacts must be traced, notified and treated, particularly as many infections are asymptomatic.

A follow-up interview (possibly by telephone) should be held in order to assess adherence to therapy and partner notification. A routine test of cure is not necessary after treatment with azithromycin or doxycycline, except in pregnant women or where symptoms persist or re-infection is suspected. NAATs may remain positive for some time after treatment, as they detect non-viable organisms, so a test of cure should be deferred until 6 weeks after the start of treatment.

image Gonorrhoea

Neisseria gonorrhoeae is a Gram-negative intracellular diplococcus (Fig. 12.3), which infects the urethra, endocervix, rectum, pharynx and conjunctiva. It is transmitted by direct inoculation of infected secretions from one mucous membrane to another. Up to 50% of infected women and 10% of infected men are asymptomatic. Co-infection with CT is common, occurring in 20% of men and 40% of women with gonorrhoea (GC).

image
Figure 12.3 Neisseria gonorrhoeae. Gram-negative intracellular diplococci. (Courtesy of Dr B. Goh.)
image Non-gonococcal urethritis

Non-gonococcal urethritis (NGU) in men is usually characterized by a urethral discharge and dysuria. There are a number of causes, many of which are sexually transmitted; the most common of these is C. trachomatis, which is discussed above. Other causes are Mycoplasma genitalium, Ureaplasma urealyticum, Trichomonas vaginalis (TV), herpes simplex virus (HSV) 1 and 2, and adeno­viruses, in that order of frequency. Studies investigating the aetiology of NGU have consistently identified no known cause in over 60% of cases. Non-sexually transmitted causes of NGU may be urinary tract infections (UTIs), foreign bodies and strictures.

image Clinical features

The incubation period is usually 2–3 weeks. The main symptom is a mucoid or mucopurulent urethral discharge, which may be worse on waking, when there may be crusting at the meatus. Dysuria is common but not universal. Discomfort or itching within the urethra may be present.

image Diagnosis

NAAT for N. gonorrhoeae and for C. trachomatis should be performed in all men with symptoms of urethritis on either an FVU sample or urethral swab. Microscopy of Gram-stained urethral secretion showing five or more polymorphonuclear leucocytes per high-power (×1000 oil-immersion lens) field is diagnostic. Men who are symptomatic but have no objective evidence of urethritis should be re-examined and tested after holding their urine overnight. Testing for TV and HSV is not routinely performed and there are no commercial tests available for M. genitalium and U. urealyticum. A mid-stream specimen of urine (MSU) should be taken if symptoms are suggestive of a UTI (urinary frequency, nocturia, urgency, haematuria).

image Management

Therapy for NGU is with either doxycycline 100 mg ×2 daily for 7 days or azithromycin 1 g orally as a single dose. Abstinence from sex for at least 7 days should be advised. All sexual contacts should be notified, examined and treated. Follow-up is only indicated if CT is confirmed or if symptoms persist.

Recurrent/persistent NGU

This is defined as persistent or recurrent symptomatic urethritis occurring 30–90 days following treatment of acute NGU, and occurs in 10–20% of cases. The aetiology is probably multifactorial but M. genitalium and T. vaginalis are likely causes. It is necessary to ensure that there is still objective evidence of urethritis, that there was good adherence to NGU treatment with sexual abstinence, and that sexual partners were also treated. If there is no objective evidence of urethritis, patients should be reassured and further antibiotic therapy avoided. Subsequent treatment needs to cover M. genitalium and T. vaginalis. The recommended treatment is azithromycin 500 mg orally as a single dose, followed by 250 mg daily for 4 days with metronidazole 400 mg ×2 daily for 5 days.

image Pelvic inflammatory disease

Pelvic inflammatory disease (PID) results when infections ascend from the cervix or vagina into the upper genital tract. It is most frequent in young (under 25 years) sexually active women. It includes endometritis, salpingitis, tubo-ovarian abscess and pelvic peritonitis. The main causes are C. trachomatis and N. gonorrhoeae, but these are identified in less than half of the cases of PID in the UK. M. genitalium has been associated with PID and anaerobes have also been implicated. Even in women with laparoscopically proven PID, often no bacterial cause is found. PID has serious long-term sequelae due to tubal damage and pelvic adhesions, resulting in tubal infertility, increased risk of ectopic pregnancy and chronic pelvic pain. The risk of sequelae increases with more severe and multiple episodes of PID. Tubal infertility occurs in 10–12% of women after one episode of PID and increases to 50–60% after three or more episodes. The risk of ectopic pregnancy is increased 6–10-fold and abdominal or pelvic pain for longer than 6 months occurs in 18% of women.

image Clinical features

The onset of symptoms often occurs in the first part of the menstrual cycle. Lower abdominal pain, usually bilateral, is the most common symptom, with increased vaginal discharge, irregular bleeding, deep dyspareunia and dysuria being present in some women. There may be a mucopurulent cervical discharge with contact bleeding. Lower abdominal tenderness and adnexal and cervical motion tenderness on bimanual examination are the most common signs.

image Diagnosis

The diagnosis is usually made on the clinical findings of lower abdominal pain, with supportive symptoms of increased vaginal discharge and abnormal bleeding, and cervical motion and/or adnexal tenderness on bimanual examination. However, such a clinical diagnosis has a specificity of only 65–70%. The differential diagnosis includes ectopic pregnancy, acute appendicitis, endo­metriosis, UTI and irritable bowel disease.

Investigations should include microscopy of Gram-stained vaginal discharge for bacterial vaginosis (BV), NAAT and culture for N. gonorrhoeae, and NAAT for C. trachomatis. There are no commercial tests available for M. genitalium. A pregnancy test should be performed on all women suspected of having PID, as ectopic pregnancy is a differential diagnosis. An MSU should be taken if symptoms are suggestive of a UTI (urinary frequency, nocturia, urgency, haematuria).

image Management

Early diagnosis and treatment reduce the risk of long-term sequelae, so empirical treatment should be started before microbiology results are known. A broad-spectrum antibiotic regimen is needed to cover the main bacterial causes. The recommended regimens are: single-dose ceftriaxone 500 mg i.m. with doxycycline 100 mg ×2 daily and metronidazole 400 mg ×2 daily for 14 days; or ofloxacin 400 mg ×2 daily and metronidazole 400 mg ×2 daily for 14 days. Abstinence from sex for at least 14 days should be advised. All sexual contacts should be notified, examined and treated.

Those with moderate or severe clinical findings should be reviewed within 2–3 days to ensure they are improving on treatment. Lack of response requires further investigation and possible admission for intravenous therapy and/or surgical intervention. All women should be seen after 2 weeks in order to assess symptom resolution, adherence to therapy and partner notification.

image Epididymo-orchitis

Acute epididymo-orchitis is a clinical syndrome consisting of pain, swelling and inflammation of the epididymis that can extend into the testis. It is caused mainly by extension of infection from the urethra or the bladder. In men under 35 years, C. trachomatis and N. gonorrhoeae are the main causes, but in men over 35 years, it is more commonly a complication of a UTI. Mumps is another cause of epididymo-orchitis in non-immune men. The most common differential diagnosis is torsion of the spermatic cord, which is a urological emergency.

image Clinical features

The typical presentation is subacute onset of unilateral scrotal pain and swelling. There may also be symptoms of a urethral discharge and dysuria but these are often absent. On examination, there is tenderness and usually palpable swelling of the epididymis. There may also be some tenderness and swelling of the testicle, with oedema and erythema of the overlying scrotal skin. A urethral discharge may be present.

image Diagnosis

The diagnosis is usually made on the above clinical findings. The main differential diagnosis is testicular torsion.

Investigations include a NAAT and culture for N. gonorrhoeae and a NAAT for C. trachomatis. If microscopy of Gram-stained urethral secretions shows five or more polymorphonuclear leucocytes per high-power (×1000 oil-immersion lens) field, this indicates the diagnosis of NGU. If intracellular Gram-negative diplococci are present, this is suggestive of GC. An MSU should be taken if symptoms are suggestive of a UTI (urinary frequency, nocturia, urgency, haematuria) and in older men.

image Management

As empirical treatment should be started before microbiology results are known, a broad-spectrum antibiotic regimen is needed to cover the main bacterial causes. In younger men, where an STI is the likely diagnosis, the recommended regimen is single-dose ceftriaxone 500 mg i.m. with doxycycline 100 mg ×2 daily for 14 days. Where a UTI is the more likely diagnosis, ofloxacin 200 mg ×2 daily for 14 days should be prescribed. Abstinence from sex for at least 14 days should be advised. All sexual contacts should be notified, examined and treated.

Patients should be reassessed after 3 days if there is no improvement in their symptoms, as such lack of response requires further investigations. All should be seen after 2 weeks in order to assess symptom resolution, adherence to therapy and partner notification.

image Bacterial vaginosis

Bacterial vaginosis (BV) is the most frequent cause of vaginal discharge among women of childbearing age. A BV prevalence of 9% has been reported in women attending general practice for cervical cytology screening and in 15% of pregnant women in the UK. BV develops when the normal Lactobacilli-dominant vaginal flora are replaced by an overgrowth of other bacteria, including Gardnerella vaginalis, anaerobes, mycoplasmas and Mobiluncus spp. It is not regarded as a sexually transmitted disease. BV in pregnancy is associated with an increased risk of miscarriage and preterm birth. It also increases the risk of acquisition and transmission of HIV. Up to 50% of women with BV have no symptoms and, as it is not regarded as an STI, it is not necessary to look for or treat asymptomatic BV.

image Clinical features

The symptoms are an increased vaginal discharge and offensive fishy odour. On examination, there is a creamy-white homogeneous discharge, which may be slightly frothy (due to the volatile amine production by the bacteria, and which is responsible for the characteristic odour) and adherent to the vaginal walls (Fig. 12.5). Visible inflammatory changes are not seen with BV, so there should be no vaginal inflammation.

image
Figure 12.5 Bacterial vaginosis. Homogenous creamy-white vaginal discharge, which may be slightly frothy and adherent to the vaginal walls.
image Candidiasis

Candida is a ubiquitous organism and is not classified as an STI. Vulvovaginal Candida infection is extremely common; about 75% of women have at least one episode of symptomatic candidiasis in their lifetime. About 20% of asymptomatic women are colonized with Candida, and this figure rises to 30–40% in pregnancy and uncontrolled diabetes. Predisposing factors for symptomatic infection include pregnancy, diabetes, the use of broad-spectrum antibiotics and corticosteroids, and immunosuppression. Candida albicans causes 90% of vaginal yeast infections, with Candida glabrata and other Candida species causing the remainder. Male sexual partners of women with candidiasis can contract transient penile colonization (and may develop penile rashes) following sex due to direct inoculation from the vagina.

image Trichomoniasis

Trichomonas vaginalis (TV) is the most common STI worldwide but it is much rarer in Western Europe and Australasia. The organism is a flagellated protozoon that is sexually transmitted. In women, it infects the vagina and urethra; in men, it infects the urethra and sub-preputial sac. Nearly all infected men are asymptomatic, as are 10–50% of women. TV in pregnancy is associated with an increased risk of preterm birth and low birth weight, and it increases the risk of acquisition of HIV.

image Human papillomavirus – anogenital warts

Anogenital warts are painless, benign, epithelial tumours and are a common STI. The causative agent is human papillomavirus (HPV) types 6 and 11. Genital HPV infection is acquired by direct skin-to-skin contact during sex with a person who has either clinical or subclinical infection. Subclinical infection is very common in young sexually active people, with rates of up to 20%. Anogenital warts are the ‘tip of the iceberg’, occurring in only about 1% of those with subclinical infection.

Warts due to HPV 6 and 11 do not undergo malignant transformation. The main oncogenic HPV types are 16 and 18. These lead to subclinical infection, not genital warts, and cause the majority of cases of cervical and other anogenital cancers (see p. 265). Neonates may acquire HPV from an infected birth canal, which may result either in anogenital warts or in laryngeal papillomatosis.

image Clinical features

Anogenital warts have a long incubation period; the average is 3 months but it can extend to years. The warts first appear at sites of trauma during sex, so in males they tend to appear around the prepuce and glans; from there, they can spread to the urethra and down the penile shaft. In women, they usually start at the fourchette and then spread to the vulva and perineum (Fig. 12.7). Perianal lesions are common in both sexes but are more common in MSM. Warts on mucous membranes tend to be soft and non-keratinized, whereas those on the hair-bearing skin tend to be firm and keratinized.

image
Figure 12.7 Genital warts on the fourchette and perineum.

Warts tend to increase in size and number during pregnancy or in immunosuppressed patients.

image Molluscum contagiosum

Molluscum contagiosum (see pp. 1344–1345) is a large DNA virus. It causes small (typically 2–5 mm in diameter), benign, smooth papules with central umbilication. It is spread via direct skin-to-skin contact. When it is transmitted sexually, the lesions are usually multiple and present on the labia majora, penile shaft, pubic region, lower abdomen and upper inner thighs.

image Diagnosis

The diagnosis is made on the characteristic clinical appearance. As it is a sexually acquired condition, investigations for other STIs should include NAAT for N. gonorrhoeae and NAAT for C. trachomatis, and serology for syphilis and HIV.

image Management

Molluscum infection is often self-limiting, resolving naturally. Treatment options, if required, are cryotherapy, podophyllotoxin cream or imiquimod cream. The creams have the advantage of being self-applied home therapies. Podophyllotoxin and imiquimod should be avoided in pregnancy. Patients should be advised about the risks of autoinoculation of the virus and discouraged from shaving or waxing the pubic hair in order to prevent further spread. No routine follow-up or partner notification is required unless any other STIs are identified.

image Herpes simplex

Genital herpes (also see pp. 247–249) is the most common cause of genital ulceration in all countries worldwide. The peak incidence for primary infection is in 16–24-year-olds. Women acquire the infection more frequently than men, probably because of the larger surface area of susceptible mucous membrane on the vulva. Transmission occurs from the mucous membrane of a person who is shedding herpes simplex virus (HSV), many of whom will be asymptomatic. Only about 20% of people with serological evidence of genital herpes give a clinical history of herpes, suggesting that many individuals have subclinical infection.

Genital herpes can be due to HSV type 1 or type 2. It is possible to be co-infected with both HSV-1 and HSV-2. HSV-1 infection may be spread from an infected genital tract or from orolabial lesions via orogenital sex. HSV-2 is almost always transmitted via genital-to-genital contact. In the UK, more than 50% of primary HSV is due to HSV-1.

During the primary infection, the virus ascends the peripheral sensory nerves supplying the area of inoculation and establishes latency in the dorsal root ganglia, thus allowing future reactivation and recurrences.

image Clinical features

Initial episode is the first occurrence of either HSV-1 or HSV-2. This is sub-divided as below, depending on whether or not the person has had prior exposure to the other HSV type.

Primary genital infection is the first ever exposure to either HSV type 1 or 2. It typically presents with multiple painful, shallow ulcers (Fig. 12.8). There is usually tender inguinal lymphadenopathy and systemic symptoms of viraemia, including fever, myalgia and headache. In women, external dysuria and vulval pain are the main symptoms. Ulcers may be present on the cervix and can have the appearance of a malignancy. Rectal infection may lead to severe proctitis with pain and bleeding (this is mainly seen in MSM). The lesions start to heal over a period of 10–21 days, even without treatment. Neurological complications can include aseptic meningitis and autonomic neuropathy leading to urinary retention. However, primary infection can be asymptomatic.

image
Figure 12.8 Herpes simplex rash on the penis. (Courtesy of Dr B. Goh.)

Non-primary genital infection occurs in people with previous HSV-1 or HSV-2 who then acquire the other type of genital HSV. There is some cross-protection from the prior HSV infection, resulting in a milder illness than in primary infection. Non-primary genital infections are more likely to be asymptomatic than primary infections.

Recurrent genital herpes is due to reactivation of previous HSV-1 or HSV-2 infection. HSV-2 recurs more frequently than HSV-1. The median recurrence rate in the subsequent year following a primary or non-primary infection is about one recurrence for HSV-1 and about four recurrences for HSV-2. The recurrences may be preceded by a prodrome of tingling, itching or pain in the area. On examination, there are usually a few ulcers confined to a small area and systemic symptoms are rare. Recurrences are not always noticed and asymptomatic, subclinical viral shedding can occur. However, all of these reactivated episodes are potentially infectious. Long-term studies show that symptomatic recurrences and subclinical viral shedding gradually decrease with time.

The clinical presentation of primary infection in immunosuppressed patients (including those with HIV and pregnant women) is usually more severe, with increased frequency of symptomatic and subclinical recurrences. Rarely, the infection can disseminate, causing a systemic life-threatening condition.

Genital herpes increases the acquisition and transmission of HIV and is an attributable risk in the spread of HIV. Many people with recurrent HSV develop psychological and psychosexual problems and fear rejection on disclosure of their infection to sexual partners.

image Management

Initial episode

Saltwater bathing or sitting in a warm bath is soothing and may allow women to pass urine more comfortably. Topical anaesthetic agents can also be used to ease micturition. Recommended antiviral therapies are aciclovir 400 mg ×3 daily, valaciclovir 500 mg ×2 daily or famciclovir 250 mg ×3 daily, all for 5 days. Aciclovir is the drug of choice in pregnancy and breast-feeding. If lesions are already healing, antiviral therapy will have little added effect. Secondary bacterial infection occasionally occurs and should be treated.

The natural history of HSV infection should be explained, including recurrences, subclinical viral shedding, and the potential for sexual transmission with both of these infections. Patients should be advised to avoid sex during the prodrome and recurrences. Subclinical viral shedding is most common during the first 12 months following initial HSV-2 infection and in those with frequent symptomatic recurrences. Condoms and suppressive treatment reduce the risk of transmission from subclinical viral shedding but neither completely prevents it. Consequently, disclosure should be advised in all relationships.

image Syphilis

Syphilis is a chronic systemic disease caused by Treponema pallidum (TP), a motile spirochaete. It is mainly transmitted by direct contact with an infectious lesion and enters the new host through breaches in squamous or columnar epithelium, usually during sex. Primary infection of non-genital sites may occur but is rare. It can also be transmitted by infected blood products or from mother to child during pregnancy. Hence syphilis is classified as acquired or congenital. Acquired syphilis is further subdivided into primary, secondary and early latent (all are also referred to as early or infectious syphilis, and indicate that infection has been acquired during the last 2 years), late latent (infection for more than 2 years) and tertiary syphilis (the most destructive stage, which includes cardiovascular and neurological syphilis and gummatous lesions of any organ). Congenital syphilis is also further subdivided into early (diagnosed within the first 2 years of life) and late (diagnosed over the age of 2).

The incidence varies significantly with geographic location. It is more common in low- and middle-income countries; in high-income countries, it is mainly confined to MSM. For instance, diagnoses of infectious syphilis in England between 2004 and 2013 increased by 36% in men with 74% of the infections being in MSM, whereas they decreased by 37% in women. However, syphilis still affects large numbers of pregnant women worldwide. It was estimated that, in 2008, 1.4 million pregnant women were infected worldwide, causing approximately 520 000 adverse pregnancy outcomes, including 215 000 stillbirths, 90 000 neonatal deaths, 65 000 preterm or low-birth-weight babies, and 150 000 babies with congenital infections. Antenatal screening for syphilis, followed by adequate treatment during pregnancy, can prevent many of these adverse outcomes.

image Clinical features

Primary syphilis

Between 10 and 90 days (mean 21 days) after exposure, a papule develops at the site of inoculation. This ulcerates to become a painless, firm ulcer (chancre). There is usually also a painless regional lymphadenopathy. The primary lesion may go unnoticed, especially if it is on the cervix or within the rectum. Healing occurs spontan­eously within 2–6 weeks.

image Lymphogranuloma venereum

Lymphogranuloma venereum (LGV) is an STI caused by the invasive serovars, L1, L2 and L3, of Chlamydia trachomatis. It is endemic in several tropical areas, including southern Africa, India, South-east Asia and the Caribbean. It used to be rare in Western Europe but since 2003 it has become hyper-endemic among MSM, particularly those with HIV. It is frequently associated with other STIs and acute hepatitis C infection. The main presentation in MSM is with rectal symptoms. LGV should be considered in MSM with suspected inflammatory bowel disease, as the clinical presentation can be very similar and the histological findings of LGV proctitis are similar to other causes of granulomatous proctitis, such as Crohn's disease.

image Diagnosis

Genital LGV

A swab should be taken from the ulcer base for C. trachomatis NAAT. If this is positive for C. trachomatis, genotyping for LGV should be requested. Testing for the other causes of genital ulcers should be undertaken (see Box 12.5) and should include an ulcer swab for HSV and TP PCR, and serology for syphilis, which should be repeated after the 3-month window period. A NAAT for N. gonorrhoeae, NAAT for C. trachomatis and serology for HIV should also be carried out.

Rectal LGV

A swab should be taken from the rectal mucosa for C. trachomatis NAAT. If this is positive for C. trachomatis, genotyping for LGV should be requested. Swabs should also be taken for N. gonorrhoeae NAAT, and HSV and TP PCR. Serology for syphilis and HIV should be performed, and serology for hepatitis C should be considered in view of the frequent co-infection of acute hepatitis C with LGV.

image Management

First-choice treatment is doxycycline 100 mg ×2 daily for 21 days or erythromycin 500 mg ×4 daily for 21 days. Symptoms should start to resolve within 1–2 weeks of commencing therapy. Patients should be advised to abstain from sex until completion of treatment. Sexual contacts should be notified, examined, tested and treated. Follow-up should continue until all symptoms and signs have resolved, which is usually by 3–6 weeks.

image Chancroid

Chancroid is caused by Haemophilus ducreyi. It used to be one of the most common causes of genital ulcers worldwide but its incidence has now decreased markedly. One of the drivers for its improved control and reduced incidence is its association with the acquisition of HIV infection. It is extremely rare in high-income countries.

image Clinical features

Chancroid has a short incubation period of 4–7 days. A tender papule develops at the site of inoculation, which breaks into a painful, ragged-edged ulcer with a necrotic base that bleeds easily. The usual sites of infection are the prepuce and glans penis in men and the labia minora and fourchette in women. There is often painful inguinal lymphadenopathy, which can develop into large buboes that suppurate.

image Diagnosis and management

Detection of H. ducreyi DNA using PCR is the most sensitive diagnostic test but there are no commercial assays available for this. A ‘probable diagnosis’ may be made if the patient presents the appropriate clinical picture, without evidence of syphilis or HSV.

Testing for the other causes of genital ulcers should be undertaken (see Box 12.5) and should include an ulcer swab for HSV and TP PCR, an ulcer swab for C. trachomatis NAAT with geno­typing for LGV if positive, and serology for syphilis, which should be repeated after the 3-month window period. A NAAT for N. gonorrhoeae, NAAT for C. trachomatis and serology for HIV should also be performed.

Single-dose regimens include azithromycin 1 g orally or ceftriaxone 250 mg i.m. Multiple-dose regimens are ciprofloxacin 500 mg ×2 daily for 3 days or erythromycin 500 mg ×4 daily for 7 days. Multiple-dose regimens should be used in HIV patients as treatment failures have been reported with single-dose therapy. Patients should be advised to abstain from sex for at least 7 days and be followed up at 3–7 days, when the ulcers should be healing. HIV-infected patients should be monitored closely, as healing may be slower. Sexual partners should be notified, examined and treated epidemiologically, as asymptomatic carriage has been reported.

image Donovanosis

Donovanosis (also known as granuloma inguinale) is exceedingly rare and is confined to a few countries in South-east Asia, South America and the Caribbean. It is caused by Klebsiella granulomatis.

image Clinical features

Nodules at the site of inoculation develop into friable, non-painful ulcers or hypertrophic lesions that increase in size. There is enlargement of the inguinal lymph nodes, which may ulcerate.

image Diagnosis and management

The diagnosis is made on the presence of Donovan bodies in scrapings or biopsies of the lesions. Donovan bodies are the encapsulated intracellular Gram-negative rods of Klebsiella granulomatis that are visible within histiocytes in the tissue samples. They appear deep purple when stained with Giemsa, Wright's or Leishman stains. Screening for all other STIs should be undertaken.

Antibiotic treatment should be given for a minimum of 3 weeks and until the lesions have healed. Regimens include azithromycin 1 g weekly or 500 mg daily, or ciprofloxacin 750 mg ×2 daily. Patients should be advised to abstain from sex for at least 3 weeks and be followed up until the lesions have fully resolved. Sexual partners should be notified, examined and treated if necessary.

image Pediculosis pubis

The pubic louse (Phthirus pubis) is able to attach tightly to the pubic and coarse body hair. It can also attach to eyelashes and eyebrows. It is host-specific and is transferred by close bodily contact. Although infestation may be asymptomatic, the most common complaint is of itch due to hypersensitivity to the louse bites.

image Diagnosis and management

Lice may be seen on the pubic and body hairs. They resemble small scabs or freckles but can be seen moving. The eggs (nits) are laid at the hair base and are strongly adherent to the hairs. Screening for other STIs should include NAAT for N. gonorrhoeae, NAAT for C. trachomatis and serology for syphilis and HIV.

Treatment should be applied to all areas of the body, including facial hair if present. Malathion 0.5% should be left on for at least 2 hours, and permethrin 1% left on for 10 minutes. A second application is usually advised after 3–7 days. Permethrin is safe in pregnancy. Sexual partners should be examined and treated if infected.

image Scabies

This is discussed on page 1347.

Further reading

Brunham RC, Gottlieb SL, Paavonen J. Pelvic inflammatory disease. New Engl J Med 2015; 372:2039–2208.

Chow EP, Read TR, Wigan R et al. Ongoing decline in genital warts among young heterosexuals 7 years after the Australian human papillomavirus (HPV) vaccination programme. Sex Transm Infect 2015; 91:214–219.

Garland SM. The Australian experience with the human papillomavirus vaccine. Clin Ther 2014; 36:17–23.

Hawkes SJ, Gomez GB, Broutet N. Early antenatal care: does it make a difference to outcomes of pregnancy associated with syphilis? PLoS One 2013; 8:e56713.

Hofstetter AM, Rosenthal SL, Stanberry LR. Current thinking on genital herpes. Curr Opin Infect Dis 2014; 27:75–83.

Ingles DJ, Pierce Campbell CM, Messina JA et al. Human papillomavirus virus (HPV) genotype- and age-specific analyses of external genital lesions among men in the HPV Infection in Men (HIM) study. J Infect Dis 2015; 211:1060–1067.

Kreimer AR, Pierce Campbell CM, Lin H-Y et al. Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study. Lancet 2013; 382:877.

Merin A, Pachankis JE. The psychological impact of genital herpes stigma. J Health Psychol 2011; 16:80–90.

Mitchell C, Prabhu M. Pelvic inflammatory disease: current concepts in pathogenesis, diagnosis and treatment. Infect Dis Clin North Am 2013; 27:793–809.

Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome

Epidemiology and Pathogenesis

image Epidemiology

Since the first description of AIDS in 1981 and the identification of the causative organism, HIV, in 1983, more than 78 million people are estimated to have been infected and 39 million people have died. At least 35 million people worldwide are living with HIV infection. Highly active anti-retroviral therapy (ART) has dramatically reduced mortality for those who are able to access care, transforming HIV from a universally fatal infection into a long-term manageable condition, with a consequent rise in global prevalence. Effective therapy since 2001 has also reduced infectiousness, and new infections globally have fallen by 38%, although there is considerable geographical diversity. Sub-Saharan Africa remains the most seriously affected, and in Eastern Europe and parts of central Asia, infection rates continue to rise. The human, societal and economic costs are huge. HIV is a major contributor to the global burden of disease, being the leading cause of disability-adjusted life-years for people aged 30–45 years. Demographics of the epidemic have varied greatly, influenced by social, behavioural, cultural and political factors. Current global estimates suggest that 38% of people living with HIV are on ART, but that, for each individual starting therapy, there are two new infections, highlighting the size of the problem and the global inequalities that exist in healthcare.

In the UK, falling death rates and sustained new infections mean that the total number of people living with HIV continues to rise. In 2013, 107 000 people were estimated to be living with HIV and 6000 were newly diagnosed. Individuals accessing care almost doubled in number from a decade earlier, and MSM and culturally diverse heterosexual populations from sub-Saharan Africa are the two largest groups of people living with HIV. Of those diagnosed with HIV in the UK, 30% are women. As mortality rates fall, the population living with HIV is becoming older, with 1 in 4 now aged 50 years and over.

Approximately one-quarter of those with HIV infection in the UK are undiagnosed and unaware of their infection, which contributes to late diagnosis, poorer clinical outcomes and onward transmission. Late diagnosis is now the most common cause of HIV-related morbidity and mortality in the UK. The proportion and number of people diagnosed late (with a CD4 count of <350 cells/mm3 within 3 months of their diagnosis) declined from 57% in 2004 to 42% in 2013. Reducing late and undiagnosed HIV through wider testing, particularly in patients presenting with clinical conditions that are associated with HIV and those in areas with high seroprevalence, is critical to both the individual and public health (Box 12.8).

image Box 12.8

HIV testing

UK guidelines on where and who to test

HIV-associated indicator conditions

Respiratory

• Tuberculosis, pneumocystisa, bacterial pneumonia, aspergillosis

Neurology

• Cerebral toxoplasmosisa, primary cerebral lymphomaa, cryptococcal meningitisa, progressive multifocal leucoencephalopathya, aseptic meningitis/encephalitis, cerebral abscess, space-occupying lesion of unknown cause, Guillain–Barré syndrome, transverse myelitis, peripheral neuropathy, dementia

Dermatology

• Kaposi's sarcomaa, severe/recalcitrant seborrhoeic dermatitis, severe/recalcitrant psoriasis, multidermatomal/recurrent herpes zoster

Gastroenterology

• Persistent cryptosporidiosisa, oral candidiasis, oral hairy leukoplakia, chronic diarrhoea of unknown cause, weight loss of unknown cause, Salmonella, Shigella, Campylobacter, hepatitis B infection, hepatitis C infection

Oncology

• Non-Hodgkin's lymphomaa, anal cancer, anal intraepithelial dysplasia, lung cancer, seminoma, head and neck cancer, Hodgkin's lymphoma, Castleman's disease

Gynaecology

• Cervical cancera, vaginal intraepithelial neoplasia, cervical intraepithelial neoplasia, grade 2 or above

aAIDS-defining condition.

(From http://guidance.nice.org.uk/PH33 ; http://www.nice.org.uk/guidance/PH34; http://www.bhiva.org/HIVTesting2008.aspx.)

Routes of acquisition

Despite the fact that HIV can be isolated from a wide range of body fluids and tissues, the majority of infections are transmitted via semen, cervical secretions and blood. The most significant marker for transmission risk is the HIV viral load, which is highest in acute infection, and reduced by effective ART. HIV-associated stigma and discrimination, gender-based violence and, in some countries of the world, the legal position for those at especially high risk can all impede access to appropriate services and increase the risks of transmission and acquisition of HIV.

Sexual intercourse (vaginal and anal)

Globally, heterosexual intercourse accounts for the vast majority of infections, and coexistent STIs, especially those causing genital ulceration, enhance transmission. Passage of HIV appears to be more efficient from men to women, and to the receptive partner in anal intercourse, than vice versa. In the UK, sex between men accounts for over half of the new diagnoses reported, but there is a consistent rate of heterosexual transmission. In Central and sub-Saharan Africa, the epidemic has always been heterosexual and more than half of infected adults in these regions are women. South-east Asia and the Indian subcontinent are experiencing an explosive epidemic, driven by heterosexual intercourse and a high incidence of other STIs.

Mother-to-child transmission (transplacental, perinatal, breast-feeding)

Vertical transmission is the most common route of HIV infection in children. European studies suggest that, without intervention, 15% of babies born to HIV-positive mothers are likely to be infected, although rates of up to 40% have been reported from Africa and the USA. Increased vertical transmission is associated with advanced disease in the mother, maternal viral load, prolonged and premature rupture of membranes, and chorioamnionitis. Transmission can occur in utero, although the majority of infections take place perinatally. Breast-feeding has been shown to double the risk of vertical transmission. In the developed world, interventions to reduce vertical transmission, including screening for infection in pregnancy, the use of anti-retroviral agents (ARVs) and the avoidance of breast-feeding, have led to a dramatic fall in the numbers of infected children. In the UK, the risk of vertically transmitted infection is 1 : 1000. The lack of access to these interventions in resource-poor countries in which 90% of infections occur is a major global issue.

Contaminated blood, blood products and organ donations

Screening of blood and blood products was introduced in 1985 in Europe and North America. Prior to this, HIV infection was associated with the use of clotting factors (for haemophilia) and with blood transfusions. In some parts of the world where blood products may not be screened and in areas where the rate of new HIV infections is very high, transfusion-associated transmission continues to occur.

Contaminated needles (intravenous drug misuse, injections and needle-stick injuries)

The practice of sharing needles and syringes for intravenous drug use continues to be a major route of transmission of HIV in parts of South-east Asia, Latin America and Eastern Europe. In some areas, including the UK, successful education and needle exchange schemes have reduced the rate of transmission by this route. Iatrogenic transmission from needles and syringes used in developing countries is reported. Healthcare workers have a risk of approximately 0.3% following a single needle-stick injury with known HIV-positive blood.

There is no evidence that HIV is spread by social or household contact or by blood-sucking insects such as mosquitoes and bed bugs.

image Pathology

The virus

HIV belongs to the lentivirus group of the retrovirus family. There are two types, HIV-1 and HIV-2. HIV-1 is the most frequently occurring strain globally. HIV-2 is almost entirely confined to West Africa, although there is some spread to Europe, particularly France and Portugal. HIV-2 has only 40% structural homology with HIV-1 and, although it is associated with immunosuppression and AIDS, it appears to take a more indolent course than HIV-1. Many of the drugs that are used in HIV-1 are ineffective in HIV-2. The structure of HIV is shown in Figure 12.10.

image
Figure 12.10 Structure of HIV. Two molecules of single-stranded RNA are shown within the nucleus. The reverse transcriptase polymerase converts viral RNA into DNA (a characteristic of retroviruses). The protease includes integrase (p32 and p10). The p24 (core protein) levels can be used to monitor HIV disease. p17 is the matrix protein; gp120 is the outer envelope glycoprotein, which binds to cell surface CD4 molecules; and gp41, a transmembrane protein, influences infectivity and cell fusion capacity.

Retroviruses are characterized by possession of the enzyme reverse transcriptase, which allows viral RNA to be transcribed into DNA and thence incorporated into the host cell genome. Reverse transcription is an error-prone process with a significant rate of mis-incorporation of bases. This, combined with a high rate of viral turnover, leads to considerable genetic variation and a diversity of viral subtypes or clades. On the basis of DNA sequencing, HIV-1 is divided into four distinct strains, which represent four independent cross-species transfers: three (M, N and O) based on the chimpanzee-related strains of simian immunodeficiency virus (SIV) and one (P) that may represent chimpanzee to gorilla to human transmission.

image Pathogenesis

The interrelationship between HIV and the host immune system is the basis of the pathogenesis of HIV disease. At the time of initial exposure, the virus is transported by dendritic cells from mucosal surfaces to regional lymph nodes, where permanent infection is established, usually by one ‘founder virus’. The host cellular receptor that is recognized by HIV surface glycoprotein gp120 is the CD4 molecule, which defines the cell populations that are susceptible to infection (Fig. 12.11). The interaction between CD4 and HIV gp120 surface glycoprotein, together with host chemokine CCR5 or CXCR4 co-receptors, is responsible for HIV entry into cells. Although CCR5 CD4 memory T lymphocytes within all body systems are susceptible to infection and depletion, those found in the gastro­intestinal tract are heavily infected early in the process. These lymphocytes become rapidly depleted, leading to compromised mucosal immune function, and thus allowing microbial lipopolysaccharides to enter the circulation. HIV infection that is independent of CD4 receptors can occur in astrocytes and renal epithelial cells, leading to end-organ damage.

image
Figure 12.11 HIV entry and replication in CD4 T lymphocytes. (a) Binding: the virus binds to host CD4 receptor molecules via the envelope glycoprotein gp120 and co-receptors CCR5 and CXCR4. (b) Fusion: a subsequent conformational change results in fusion between gp41 and the cell membrane. (c) Reverse transcription: entry of the viral capsid is followed by uncoating of the RNA. DNA copies are made from both RNA templates. DNA polymerase from the host cell leads to the formation of double-stranded DNA (dsDNA). (d) Integration: in the nucleus, virally encoded DNA is inserted into the host genome. (e) Transcription: regulatory proteins control transcription (an RNA molecule is now synthesized from the DNA template). (f) Budding: the virus is re-assembled in the cytoplasm and budded out from the host cell.

Studies of viral turnover have demonstrated a virus half-life in the circulation of about 6 hours. To maintain observed levels of plasma viraemia, 108–109 virus particles need to be released and cleared daily. Virus production by infected cells lasts for about 2 days and is probably limited by the death of the cell, owing to direct HIV effects. This links HIV replication to the process of CD4 destruction and depletion. Progressive loss of activated CD4 T lymphocytes due to killing by CD8 cells is a key factor in the immunopathogenesis of HIV. Natural killer cells are involved in the host immune response, although escape mutations within the virus population compromise their antiviral effects. The production of neutralizing antibodies, which, in some people, can be against several viral subtypes, occurs at about 12 weeks after infection.

Resulting cell-mediated immunodeficiency leaves the host open to infections with intracellular pathogens, while coexisting antibody abnormalities predispose to infections with capsulated bacteria. HIV is associated with immune activation, a long-term inflammatory state, which is a key driver of disease progression. T-cell activation is observed from the earliest stages of infection, which, in turn, leads to an increase in the numbers of susceptible CD4-bearing target cells that can become infected and destroyed. This inflammatory state is associated with HIV itself, with co-pathogens such as cytomegalovirus, and with the translocation of microbial products, in particular lipopolysaccharides, from the gut into the systemic circulation following HIV destruction of normal mucosal immunity. Raised levels of inflammatory cytokines and coagulation system activation occur. These inflammatory responses may remain, despite effective ART, and play a role in HIV-associated end-organ damage, as well as raising the risks of myocardial infarction and some malignancies.