Sexually Transmitted Infections PDF

SECTION FOUR Clinical manifestation and diagnosis of infections by body system Sexually transmitted infections Introduction...

SECTION FOUR Clinical manifestation and diagnosis of infections by body system Sexually transmitted infections Introduction 22 Sexually transmitted infections usually cause diseases In some instances, sexually transmitted infections (STIs) may not result in overt disease symptoms, such as in the early stages of human immunodeficiency virus (HIV) infection and asymptomatic gonorrhoea in females. This is particularly concerning as people with asymptomatic or unreported STIs are unlikely to receive treatment, thus facilitating further cycles of infection and spread. While STIs are of major medical importance throughout the world, HIV infection has had the greatest global impact, estimated to affect nearly 37 million people in 2015. In addition to HIV, new cases of other STIs occur globally with alarming frequency (hundreds of millions of new cases) each year. STIs are difficult to control resulting from each primary STD case depends on a variety This is typified by the situation in the UK where there were of behavioural factors since the number of sexual partners 472 038 new STD cases reported by genitourinary medicine acquired by a given individual (i.e. the level of promiscuity) clinics in 2014 / 2015. A similar situation exists in other varies considerably. Those who have many sexual partners countries, including the USA. The reasons for this increase are both more likely to acquire and to transmit infection include: and play a key role in the persistence of such infections in the community of sexually active individuals. People with increasing density and mobility of human populations many sexual partners are therefore an obvious target for the difficulty of engineering changes in human sexual treatment and education about safer sex practices, such as behaviour condom use. the absence of vaccines for almost all STIs, except for the human papillomavirus (HPV) vaccine. HIV infection, syphilis, gonorrhoea, chlamydia and genital Various host factors influence the risk of wart infections are some of the STIs included in national and acquiring an STI global surveillance programmes. It is not surprising that the type of sexual activity is important The most common STIs are listed in Table 22.1. Table 22.2 or that genital lesions or ulcers increase the risk of acquiring gives examples of the strategies used by the pathogens to infections such as HIV. In addition, it is well reported that overcome host defences. uncircumcised men have a higher risk of infection. STIs do not necessarily occur singly, and the possibility STIS AND SEXUAL BEHAVIOUR of multiple infections must always be borne in mind. For The general principles of entry, exit and transmission of the instance, syphilis can accompany gonorrhoea, and there is pathogens that cause STIs are set out in Chapter 14. evidence that genital herpes may be reactivated during an attack of gonorrhoea. The spread of STIs is inextricably linked with sexual behaviour SYPHILIS There are therefore many more opportunities for controlling Syphilis is caused by the spirochete STIs than, for instance, respiratory infections. Infected but Treponema pallidum asymptomatic individuals play an important role, and Treponema pallidum is closely related to the treponemes that important determinants are promiscuity and sexual practices cause the non-venereal infections of pinta and yaws (Table involving contact between different orifices and mucosal 22.3; Fig. 22.1). T. pallidum has a worldwide distribution, and surfaces (see Ch. 14). For example, transmission between syphilis remains a serious problem not only in resource-rich heterosexuals or men who have sex with men (MSM) can countries but also especially in resource-poor areas, due to take place following oral or anal intercourse. The gonococcus, the serious sequelae and the risk of congenital infection. In for instance, causes pharyngitis and proctitis, although it the USA during 2014–2015 the rate of syphilis in women infects stratified squamous epithelium less readily than increased by almost 30% and congenital syphilis increased columnar epithelium. As described more fully in Chapter 33, by 6%, a trend that continues currently and has also been calculations regarding the number of infected secondary cases seen in the UK. 241 ERRNVPHGLFRVRUJ  22 CHAPTER Sexually transmitted infections Table 22.1 The most common sexually transmitted infections (STIs) Organism Disease Comment Treatment Papillomaviruses (types Genetic warts, dysplasias Vaccines available; most common Podophyllin 6, 11, 16 and 18) STI in the US Imiquimod Cryotherapy Cidofovir gel Chlamydia trachomatis D-K serotypes (non-specific Most common easily cured STI in Azithromycin, doxycycline urethritis); L serotypes the US; urethritis very common; (lymphogranuloma venereum) lymphogranuloma venereum primarily in resource-poor countries Candida albicans Vaginal thrush Predisposing factors Clotrimazole, fluconazole Trichomonas vaginalis Vaginitis, urethritis Often asymptomatic; causes ca. Metronidazole 50% of curable vaginal infections worldwide Herpes simplex virus Genital herpes Problem of latency and reactivation Aciclovir, valaciclovir, types 1 and 2 famciclovir Neisseria gonorrhoeae Gonorrhoea 2nd most most commonly Cephalosporin (e.g. reported notifiable disease in the ceftriaxone) in the US; quinolone resistance common HIV AIDS Worldwide problem Antiretroviral drugs Treponema pallidum Syphilis Incidence increasing in the US Penicillin Hepatitis B virus Hepatitis B Vaccine available Antivirals include lamivudine, tenofovir, entecavir, adefovir, interferon alpha Haemophilus ducreyi Chancroid Mainly tropical Azithromycin, ceftriaxone Sarcoptes scabiei Genital scabies Human mite burrows into upper Permethrin cream skin layer Phthirus pubis Pubic lice No. 1 louse infestation in US adults Permethrin cream Table 22.2 Strategies adopted by sexually transmitted microorganisms to combat host defences Host defences Microbial strategies Examples Integrity of mucosal surface Specific attachment mechanism Gonococcus or chlamydia to urethral epithelium Urine flow (for urethral Specific attachment; induce own uptake Gonococcus infection) and transport across urethral epithelial surface in phagocytic vacuole Infection of urethral epithelial or Herpes simplex virus (HSV), chlamydia subepithelial cells Phagocytes (especially Induce negligible inflammation Treponema pallidum, mechanism unclear, perhaps polymorphs) poorly activates alternative complement pathway due to sialic acid coating Resist phagocytosis Gonococcus (capsule), T. pallidum (absorbed fibronectin) Complement C3d receptor on pathogen binds C3b / d Candida albicans and reduces C3b / d-mediated polymorph phagocytosis Inflammation Induce strong inflammatory response, yet Gonococcus, C. albicans, HSV, chlamydia evade consequences Antibodies (especially IgA) Produce IgA protease Gonococcus Cell-mediated immune Antigenic variation; allows re-infection of a Gonococcus, chlamydia response (T cells, given individual with an antigenic variant lymphokines, natural killer Poorly understood factors cause ineffective T. pallidum, HIV cells, etc.) cell-mediated immune response 242 ERRNVPHGLFRVRUJ  Section Four Clinical manifestation and diagnosis of infections by body system Table 22.3 Spiral organisms of medical importance Family Genus Species Subspecies Disease Spirochaetaceae Treponema pallidum pallidum Syphilis pallidum pertenue Yaws carateum Pinta Borrelia recurrentis Relapsing fever burgdorferi Lyme disease Leptospiraceae Leptospira interrogans (serovar) Icterohaemorrhagiae Leptospirosis (Weil’s disease) A B C Figure 22.1 (A) Typical penile chancre of primary syphilis. (B) Yaws and (C) pinta are endemic in tropical and subtropical countries and are spread by direct contact. ([A] Courtesy of R.D. Catterall. [B] and [C] Courtesy of P.J. Cooper and G. Griffin.) T. pallidum enters the body through minute abrasions on An infected woman can transmit T. pallidum to her the skin or mucous membranes. Transmission of T. pallidum baby in utero requires close personal contact because the organism does Congenital syphilis is acquired after the first 3 months of not survive well outside the body and is very sensitive to pregnancy. The disease may manifest as: drying, heat and disinfectants. Horizontal spread (see Ch. serious infection resulting in intrauterine death 14) occurs through sexual contact, and vertical spread via congenital abnormalities, which may be obvious at birth transplacental infection of the fetus (see Ch. 24). silent infection, which may not be apparent until about 2 Local multiplication leads to plasma cell, polymorph and years of age (facial and tooth deformities). macrophage infiltration, with later endarteritis. The bacteria multiply very slowly, and the average incubation period is Laboratory diagnosis of syphilis 3 weeks. As T. pallidum cannot be grown in vitro, laboratory diagnosis hinges on microscopy and serology. Classically, T. pallidum infection is divided into three stages Microscopy The three classical stages of syphilis are primary, secondary Exudate from the primary chancre should be examined by and tertiary syphilis (Table 22.4). However, not all patients either: go through all three stages; a substantial proportion remains dark-field microscopy immediately after collection permanently free of disease after suffering the primary or ultraviolet (UV) microscopy after staining with secondary stages of infection. The lesion of primary syphilis is fluorescein-labelled antitreponemal antibodies. illustrated in Fig. 22.1. The secondary stage may be followed The organisms have tightly wound, slender coils with pointed by a latent period of some 3–30 years, after which the disease ends and are sluggishly motile in unstained preparations. T. may recur – the tertiary stage. Unlike most bacterial pathogens, pallidum is very thin (about 0.2 mm in diameter, compared T. pallidum can survive in the body for many years despite with E. coli, which is about 1 mm) and cannot be seen in a vigorous immune response. It has been suggested that the Gram-stained preparations. Silver impregnation stains can healthy treponeme evades recognition and elimination by be used to demonstrate the organisms in biopsy material. the host by maintaining a cell surface rich in lipid. This layer is antigenically unreactive and the antigens are uncovered Serology only in dead and dying organisms when the host is then Serological tests for syphilis are the mainstay of diagnosis. able to respond. Tissue damage is mostly due to the host They are divided into non-specific and specific tests for the response. detection of antibodies in patients’ serum. Despite many years of effort, T. pallidum still cannot be cultivated in the laboratory in artificial media. It has therefore Non-specific tests (non-treponemal tests) for syphilis been difficult to study possible virulence factors at a molecular are the VDRL and RPR tests level until more recent advances in whole genome sequencing, The term non-specific is used because the antigens are which have allowed molecular characterization. not treponemal in origin, but are from extracts of normal 243 ERRNVPHGLFRVRUJ  22 CHAPTER Sexually transmitted infections Table 22.4 The pathogenesis of syphilis Stage of disease Signs and symptoms Pathogenesis Initial contact Multiplication of treponemas at site of infection; associated host response 2–10 weeks (depends on Primary chancrea at site of infection inoculum size) Primary syphilis Enlarged inguinal nodes, spontaneous Proliferation of treponemas in regional lymph nodes healing 1–3 months Secondary syphilis Flu-like illness; myalgia, headache, fever; Multiplication and production of lesion in lymph mucocutaneous rasha; spontaneous nodes, liver, joints, muscles, skin and mucous 2–6 weeks resolution membranes Treponemas dormant in liver or spleen Latent syphilis 3–30 years Re-awakening and multiplication of treponemas Tertiary syphilis Neurosyphilis; “general paralysis of the Further dissemination and invasion and host insane”, tabes dorsalis response (cell-mediated hypersensitivity) Cardiovascular syphilis; aortic lesions, heart failure Progressive destructive disease Gummas in skin, bones, testis A feature of Treponema pallidum infection is its chronic nature, which seems to involve a delicately balanced relationship between pathogen and host. a Chancre: initially a papule; forms a painless ulcer; heals without treatment within 2 months. Live treponemas can be seen in dark-ground microscopy of fluid from lesions; patient highly infectious. mammalian tissues. Cardiolipin, from beef heart, allows the Table 22.5 Serological tests for syphilis and conditions detection of anti-lipid IgG and IgM formed in the patient in associated with false-positive results response to lipoidal material released from cells damaged by Test Conditions associated with the infection, as well as to lipids in the surface of T. pallidum. false-positive results Two tests in common use today are: Non-specific Viral infection, collagen vascular the Venereal Disease Research Laboratory (VDRL) test (non-treponemal) disease, acute febrile disease, the rapid plasma reagin (RPR) test. VDRL post-immunization, pregnancy, Both are available in kit form. RPR leprosy, malaria, drug misuse Non-specific tests show up as positive within 4–6 weeks Specific Diseases associated with increased of infection (or 1–2 weeks after the primary chancre appears) (non-treponemal) or abnormal globulins, lupus and decline in positivity in tertiary syphilis or after effective FTA-ABS erythematosus, Lyme disease, antibiotic treatment of primary or secondary disease. Therefore, TP-PA autoimmune disease, diabetes these tests are useful for screening. However, they are TPHA mellitus, alcoholic cirrhosis, viral non-specific and may give positive results in conditions infections, drug misuse, and other than syphilis (biological false positives, Table 22.5). All pregnancy positive results should therefore be confirmed by a specific FTA-ABS, fluorescent treponemal antibody absorption test; MHA-TP, test. However, treatment (e.g. especially during the primary microhaemagglutination assay for T. pallidum; RPR, rapid plasma reagin test; and secondary stages) tends to result in seroreversion to these TPHA, T. pallidum haemagglutination test; TP-PA, T. pallidum particle agglutination test; VDRL, Venereal Disease Research Laboratory test. tests. Thus, with confirmed disease (see below), these tests can provide at least an indication of therapeutic efficacy. the enzyme-linked immunosorbent assay (ELISA), which Commonly used specific tests for syphilis include detects IgM and IgG the treponemal antibody test, FTA-ABS test and the fluorescent treponemal antibody absorption (FTA-ABS, the MHA-TP Fig. 22.2) test in which the patient’s serum is first absorbed These tests use recombinant proteins or treponemal antigens with non-pathogenic treponemes to remove cross-reacting extracted from T. pallidum. Tests in common use include: antibodies before reaction with T. pallidum antigens 244 ERRNVPHGLFRVRUJ  Section Four Clinical manifestation and diagnosis of infections by body system GONORRHOEA Gonorrhoea is caused by the Gram-negative coccus Neisseria gonorrhoeae (the ‘gonococcus’) This bacterium is a human pathogen and does not cause natural infection in other animals. Therefore its reservoir is human and transmission is direct, usually through sexual contact, from person to person. The organism is sensitive to drying and does not survive well outside the human host, so intimate contact is required for transmission. It is thought that a woman has a 50% chance of becoming infected after a single sexual intercourse with an infected man, whereas a man has Figure 22.2 The fluorescent treponemal antibody absorption test for a 20% chance of acquiring infection from an infected woman. syphilis. Antibody in the patient’s serum binds to bacteria and is Asymptomatically infected individuals (almost always visualized by a fluorescent dye. women, see below) form the major reservoir of infection. Infection may also be transmitted vertically from an infected mother to her baby during childbirth. Infection in babies is usually manifest as ophthalmia neonatorum (see Ch. 24). the microhaemagglutination assay for T. pallidum (MHA-TP). The gonococcus has special mechanisms to attach These tests should be used to confirm that a positive result with itself to mucosal cells a non-specific test is truly due to syphilis. Also, because they The usual site of entry of gonococci into the body is via the become positive earlier in the course of the disease, they can vagina or the urethral mucosa of the penis, but other sexual be used for confirmation when the clinical picture is strongly practices may result in the deposition of organisms in the indicative of syphilis. They tend to remain positive for many throat or on the rectal mucosa. Special adhesive mechanisms years and may be the only positive test in patients with late (Fig. 22.3) prevent the bacteria from being washed away syphilis. However, they remain positive after appropriate by urine or vaginal discharges. Following attachment, the antibiotic treatment and cannot therefore be used as indicators gonococci rapidly multiply and spread through the cervix in of therapeutic response. They can also give false-positive women, and up the urethra in men. Spread is facilitated by reactions (see Table 22.5). various virulence factors (Fig. 22.3), although the organisms do not possess flagella and are non-motile. Production of an Confirmation of a diagnosis of syphilis depends upon IgA protease helps to protect them from the host’s secretory several serological tests antibodies. Positive serological test results for babies born to infected mothers may represent passive transfer of maternal antibody Host damage in gonorrhoea results from or the baby’s own response to infection. These two possibilities gonococcal-induced inflammatory responses can be distinguished by testing for IgM and retesting at 6 The gonococci invade non-ciliated epithelial cells, which months of age, by which time maternal antibody levels internalize the bacteria and allow them to multiply within have waned. Antibody titres remain elevated in babies with intracellular vacuoles, protected from phagocytes and congenital syphilis. antibodies. These vacuoles move down through the cell and At present, several serological tests are needed to confirm a fuse with the basement membrane, discharging their bacterial diagnosis of syphilis. None of these tests distinguishes syphilis contents into the subepithelial connective tissues. Neisseria from the non-sexually transmitted treponematoses, yaws and gonorrhoeae does not produce a recognized exotoxin. Damage pinta. Western blot assays using whole T. pallidum cells as to the host results from inflammatory responses elicited by antigen are an important newer confirmatory test. the organism (e.g. lipopolysaccharide and other cell wall components; see Ch. 2). Persistent untreated infection can Treatment result in chronic inflammation and fibrosis. Penicillin is the drug of choice for treating people with Infection is usually localized, but in some cases bacteria syphilis and their contacts isolates (e.g. resistant to the bactericidal action of serum, etc.) Penicillin is very active against T. pallidum (see Table 22.1). can invade the bloodstream and so spread to other parts of For patients who are allergic to penicillin, treatment with the body. doxycycline should be given. Only penicillin therapy reliably Gonorrhoea is initially asymptomatic in many women, treats the fetus when administered to a pregnant mother. but can later cause infertility Prevention of secondary and tertiary disease depends upon early diagnosis and adequate treatment. Contact tracing with Symptoms develop within 2–7 days of infection and are screening and treatment are also important. Several STIs may characterized: be present in one patient concurrently, and patients with in the male by urethral discharge (Fig. 22.4) and pain on other STIs should be screened for syphilis. passing urine (dysuria) Congenital syphilis is completely preventable if women in the female by vaginal discharge. are screened serologically early in pregnancy (4.5 of the discharge, which shows actively motile trophozoites presence of clue cells (vaginal epithelial cells coated with (Fig. 22.12). Trichomonas may be detected by wet preparation bacteria; Fig. 22.13) microscopy of vaginal secretions or cultured from a vaginal a fishy amine-like odour. swab. Rapid point-of-care immunochromatographic tests are There is a significant increase in the numbers of G. vaginalis in available. Highly sensitive nucleic acid detection tests (NAT) the vaginal flora and a concomitant increase in the numbers are much more sensitive than wet preparation microscopy and of obligate anaerobes such as Bacteroides. some centres use NAT to test microscopy-negative samples G. vaginalis is consistently found in association with from suspected cases. vaginosis, but is also found in 20–40% of healthy women. It 251 ERRNVPHGLFRVRUJ  22 CHAPTER Sexually transmitted infections is generally present in the urethra of male partners of women causing primary oropharyngeal infection in children, and cold with vaginosis, indicating that it can be sexually transmitted. sores occur after virus reactivation. However, HSV-2 emerged G. vaginalis has also been isolated from blood cultures from as a result of independent transmission by the venereal route. women with postpartum fever. HSV-2 shows biological and antigenic differences from HSV-1 G. vaginalis has had a chequered taxonomic history, being and can be distinguished by molecular typing methods as first classified as a haemophilus, then as a corynebacterium, well as older techniques such as immunofluorescence. There reflecting the fact that it tends to be Gram-variable (sometimes is little cross-immunity. Although originally recovered from appearing Gram-negative, sometimes Gram-positive). It grows separate sites, orogenital sexual practices have obscured the in the laboratory on human blood agar in a moist atmosphere topographic difference between the strains, so that HSV-1 enriched with carbon dioxide. The organism is treated with and HSV-2 can be recovered from oral and genital sites. oral metronidazole. Species of the genus Mobiluncus appear HSV-2 is one of the most common STIs and it has been to be related to G. vaginalis and have also been implicated estimated that there are over 500 million individuals with in vaginosis. HSV-2 globally. In the USA, a Centers for Disease Control The pathogenesis of bacterial vaginosis is still unclear, (CDC) survey from 2005 to 2008 reported that HSV-2 antibody but appears to be related to factors that disrupt the normal was detected in 16% of the study population, greater among acidity of the vagina and the equilibrium between the different females. In addition, it is estimated there are nearly 800000 constituents of the normal vaginal flora. Whether any of these newly infected individuals in the USA annually. One of the or other unknown factors are sexually transmissible is unclear. worrying aspects surrounding HSV-2 is that most people do not know that they have this infection as up to 75% may not GENITAL HERPES have symptoms and therefore will not realize that they may Herpes simplex virus (HSV)-2 is the most common transmit this infection. Finally, HSV-2 infection can result in cause of genital herpes, but HSV-1 is being detected a twofold-increased risk of developing HIV infection. This is more frequently likely to be due to breaches in the mucosal barrier as a result Herpes simplex virus (HSV) is a ubiquitous infection of of the HSV ulcers. humans worldwide. HSV-1 is generally transmitted via saliva, Genital herpes is characterized by ulcerating vesicles that can take up to 2 weeks to heal The primary genital lesion on the penis or vulva is seen 3–7 days after infection. It consists of vesicles that soon breakdown to form painful shallow ulcers (Fig. 22.14). Local lymph nodes are swollen, and there may be constitutional symptoms including fever, headache and malaise. Occasionally the lesions are on the urethra, causing dysuria or pain on micturition. Healing takes up to 2 weeks, but the virus in the lesion travels up sensory nerve endings to establish latent infection in dorsal root ganglion neurones (see Ch. 25). From this site it can reactivate, travel down nerves to the same area, and cause recurrent lesions (‘genital cold sores’). Aseptic meningitis or encephalitis occurs in adults as a rare complication, and spread of infection from mother to infant at the time of delivery can give rise to neonatal disseminated Figure 22.13 Clue cells in bacterial vaginosis. herpes or encephalitis. Figure 22.14 Genital herpes. Vesicles (A) on A B the penis and (B) in the perianal area and vulva. Those on the labia minora and fourchette have ruptured to reveal characteristic herpetic erosions. (Courtesy of J.S. Bingham.) 252 ERRNVPHGLFRVRUJ  Section Four Clinical manifestation and diagnosis of infections by body system A B C Figure 22.15 Genital warts. (A) Warts on the penis are usually multiple, and on the shaft are often flat and keratinized. (B) Warts in the perianal area often extend into the anal canal. (C) Warts in the vulvoperineal area can enlarge dramatically and extend into the vagina. (Courtesy of J.S. Bingham.) Genital herpes is generally diagnosed from the clinical appearance and aciclovir can be used for treatment and prophylaxis HSV DNA can be detected and typed in vesicle fluid or ulcer swabs. More classic techniques involved virus isolation and subsequently typing the isolate by immunofluorescence using type-specific monoclonal antibodies. Recurrent genital infection is more frequent with HSV-2; therefore typing is of help in determining the prognosis. The cytopathic effect is characteristic and is generally seen within 1–2 days post-inoculation, with ballooning degenerating cells and multinucleate giant cells. HSV DNA detection methods which include type differentiation may be used, and have a much greater sensitivity than virus isolation. A number of antivirals, including oral aciclovir, valaciclovir and famciclovir Figure 22.16 Cervical dysplasia caused by papillomavirus should be can be used for treatment of severe or early lesions and removed by laser. (Courtesy of A. Goodman.) aciclovir may need to be given intravenously if there are systemic complications. Recurrent attacks are distressing and treatment options include starting an antiviral when prodromal a white plaque (Fig. 22.16) after the local application of 5% symptoms occur or alternatively taking low-dose aciclover acetic acid. Because of their association with cervical cancer, for 6 to 12 months, or one of the alternative agents, to stop especially types 16 and 18, cervical lesions are best removed or at least reduce the frequency of recurrences. by laser or loop excision. HUMAN PAPILLOMAVIRUS INFECTION HUMAN IMMUNODEFICIENCY VIRUS There are over 120 distinct types of human papillomaviruses, Human immunodeficiency virus (HIV) is a retrovirus (Table all infecting skin or mucosal surfaces, and the DNA of each 22.8), so-called because this single-stranded RNA virus contains showing less than 50% cross-hybridization with that of others. a pol gene that codes for a reverse transcriptase (Latin: retro, These are evidently ancient viral associates of humans that backwards). have evolved extensively, and many of the different types are adapted to specific regions of the body. Acquired immune deficiency syndrome (AIDS) was first recognized in 1981 in the USA Many papillomavirus types are transmitted sexually In 1981, the Communicable Disease Center, Atlanta, USA, and cause genital warts noted an increase in requests to use pentamidine for Warts (condylomata acuminata) appear on the penis, vulva Pneumocystis carinii (now classified as P. jirovecii) infection and perianal regions (Fig. 22.15) after an incubation period in previously well individuals who also suffered severe of 1–6 months (see Ch. 27). They may not regress for many infections by other normally harmless microorganisms. months and can be treated with podophyllin. The lesion on These included C. albicans oesophagitis, mucocutaneous HSV, the cervix is a flat area of dysplasia visible by colposcopy as toxoplasma CNS infection or pneumonia, and cryptosporidial 253 ERRNVPHGLFRVRUJ  22 CHAPTER Sexually transmitted infections Table 22.8 Human retroviruses Virus Comment HTLV-1 Endemic in West Indies and SW Japan; transmission via blood, sexual intercourse, vertical transmission, human milk; can cause adult T-cell leukaemia, and HTLV1-associated myelopathy, also known as tropical spastic paraparesis HTLV-2 Uncommon, sporadic occurrence; transmission via blood, sexual intercourse, vertical transmission, can cause hairy T-cell leukaemia and neurological disease HIV-1, HIV-2 Transmission via blood, sexual intercourse; responsible for AIDS. HIV-2 West African in origin, closely related to HIV-1 but antigenically distinct Human foamy virus Causes foamy vacuolation in infected cells; little is known of its occurrence or pathogenic potential Human placental virus(es) Detected in placental tissue by electron microscopy and by presence of reverse transcriptase Human genome viruses Nucleic acid sequences representing endogenous retroviruses are common in the vertebrate genome, often in well-defined genetic loci; acquired during evolutionary history; not expressed as infectious virus; function unknown; perhaps should be regarded as mere parasitic DNA Human T-cell lymphotropic virus (HTLV)-1, HTLV-2, HIV-1 and HIV-2 have been cultivated in human T cells in vitro. The human placental and genome viruses are not known as infectious agents. Retroviruses are also common in cats (FAIDS), monkeys (MAIDS), mice (mouse leukaemia) and other vertebrates. ARC, AIDS-related complex. enteritis; Kaposi’s sarcoma was also often present. Patients virus (SIV) in a Cameroonian woman, the only person in had evidence of impaired immune function, as shown by whom it has been found. The M group comprises the HIV-1 skin test anergies, and depletion of CD4-positive T-helper subtypes A to K as well as circulating recombinant forms (Th) lymphocytes. This immunodeficiency syndrome (CRF) which are due to recombination events between those appearing in an individual without a known cause such subtypes, with the N and O groups focused in western central as treatment with immunosuppressive drugs was referred Africa. The geographical prevalence of the subtypes differs, to as ‘acquired immune deficiency syndrome’ (AIDS). An with subtype B being most common in North America and internationally agreed definition of AIDS soon followed. Europe, and the non-B strains such as A and C being found Epidemics subsequently occurred in San Francisco, New more frequently in Africa. However, with increasing travel York and other cities in the USA and in the UK and the rest the subtype distribution is changing and, together with the of Europe a few years later. potential for mixed or superinfections, i.e. an HIV-infected individual becoming infected with another strain, and viral Human immunodeficiency virus that causes AIDS, was recombination events, other subtypes are being seen such isolated from blood lymphocytes in 1983 as the CRFs. The M–P groups resulted from independent It was recognized as belonging to the lentivirus (slow virus) cross-species human and ape contact in west-central Africa. group of retroviruses and related to similar agents in monkeys Transmission events were most likely to have occurred and to visnavirus in sheep and goats. The structure of the through skin and mucous membrane exposure to infected viral particle and its genome are illustrated in Fig. 22.17 and ape blood and body fluids, probably when hunting. Group M its replication mechanism in Figs 22.18 and 22.19. was found first and is the pandemic form as it comprises the Three genes, gag, pol and env, encode the matrix, capsid majority of HIV infections globally. This has been the subject and nucleocapsid structural proteins, reverse transcriptase, of molecular clock analyses, a method used in evolutionary proteases and integrase enzymes and gp120 and gp41 biology. The molecular clock hypothesis is that DNA and envelope proteins, respectively. The regulatory and accessory protein sequences evolve at a rate that is relatively constant proteins, Tat and Rev, Vif, Vpr, Vpu / x and Nef are coded over time. Due to this fact, the genetic difference between by their respective genes. Overall, there are 16 proteins that two species is proportional to the time since they shared a are involved in a variety of pairwise interactions ensuring common ancestor. efficient viral replication at key parts of the HIV life cycle, On analyzing the HIV pandemic, the onset of the HIV-1 such as virus entry, reverse transcription, virus integration, Group M infections was in the early 20th century. Having transcription and translation, virus assembly, budding and emerged between 1910 and 1930 in west-central Africa, HIV maturation (see Fig. 22.18). spread for the next 50 or so years having diversified around Kinshasa, formerly Leopoldville, the capital and largest city Human immunodeficiency virus infection started in of the Democratic Republic of the Congo. Moreover, the rivers Africa between 1910 and 1930 which serve as routes for travel and commerce would have The molecular biological evidence based on nucleic acid been a link between the chimpanzee reservoir on the banks sequencing studies has demonstrated that both HIV-1 and of the Congo river. In addition, the four groups cluster with a the closely related HIV-2 seen in West Africa arose from particular lineage of SIV cpz (cpz = chimpanzees), the original closely related primate viruses. HIV-1 is separated into reservoir of human and gorilla infections. HIV-2 is mostly four groups, namely M (major), N (new), O (outlier) and seen in West Africa and originated from sooty mangabeys. P, the latter was reported in 2009 after identifying an HIV HIV-1 may have been present in humans in central strain closely related to a gorilla simian immunodeficiency Africa for many years, but in the late 1970s it began to 254 ERRNVPHGLFRVRUJ  Section Four Clinical manifestation and diagnosis of infections by body system major structural 0 1 2 3 4 5 6 7 8 9 kb (core) protein p24gag LTR LTR matrix protein p17gag vpr tat vpu p9gag gag vif tat rev nef single-stranded RNA rev pol env host regulatory proteins virion proteins proteins gene encodes gene encodes vif virion infectivity factor LTR long terminal repeats, play essential role in replication p7gag vpr weak transcriptional activator (e.g. promote transcription) vpu required for efficient budding gag group-specific antigen proteins (virion core proteins, reverse tat transactivator protein e.g. p24, p17, p9, p7) transcriptase regulates viral transcription pol (polymerase); protease, reverse rev regulator virion proteins transcriptase and integrase lipid promote export of viral RNAs membrane from nucleus env type-specific envelope of envelope glycoproteins; gp160 precursor (host gp41env gp120env nef negative regulatory factor cleaved by proteases to form derived) important for virulence gp120 attachment protein and envelope glycoproteins gp41 fusion protein Figure 22.17 The structure and genetic map of HIV. The rev and tat genes are divided into non-contiguous pieces and the gene segments spliced together in the RNA transcript. Occasional host proteins such as major histocompatibility complex (MHC) molecules are present in the envelope. (p) is protein and (gp) is glycoprotein. About 109 HIV-1 particles are produced each day at the peak of infection, and this, together with the low fidelity of reverse transcriptase, means that new virus variants are always appearing. Mutations are seen especially in env and nef genes. Any one patient contains many variants, and drug-resistant and immune-resistant mutants emerge. spread rapidly (Fig. 22.20), possibly with changed biological and southern Africa where the figure of 24% receiving ART properties, as a result of increased transmission following in 2010 improved to 54% in 2015, just over 10 million people. major socioeconomic upheavals and migrations of people These regions also had the largest reduction in new adult HIV from Central to East Africa. Female prostitutes and male infections, 40 000 fever in 2015 than 2010. The numbers fell soldiers and workers travelling around the country played more gradually or were static in most other areas, but a near a major part in transmission. The migration pathways of the 60% increase was seen in eastern Europe and central Asia. different subtypes have been charted and subtype B, which predominates in Europe and the Americas, originated from Human immunodeficiency virus mainly infects one African strain that spread to Haiti in the 1960s and then cells bearing the CD4 glycoprotein on the cell to the USA and Europe. surface and also requires chemokine co-receptors, In the late 1980s, HIV began to appear in Asian countries, CCR5 and CXCR4 beginning with Thailand, and by 1995 explosive spread was The HIV transmission route for more than 80% of adults based on heterosexual transmission, with high infection rates in involves mucosal surfaces, in particular cervicovaginal, penile female sex workers and transmission among users of injected and rectal. The remainder may be infected by intravenous drugs in Asia. or percutaneous routes. The window period for detecting Worldwide by 2015, about 37 million adults and children the virus is 7–21 days, as HIV multiplies in the mucosa were infected with HIV including: and draining lymphoreticular tissues. The first targets are 25.5 million in sub-Saharan Africa CD4 receptor-bearing cells that include Th cells, monocytes, 5.1 million in Asia and the Pacific Langerhans cells and other dendritic cells, macrophages 1.5 million in Eastern Europe and Central Asia and microglia (Figs 22.21, 22.22). The CD4 molecule acts 2.4 million in North America, Western and Central Europe. as a high-affinity binding site for the viral gp120 envelope In 2009, nearly 3 million people were newly infected and 1.8 glycoprotein. This interacts with the gp41 transmembrane million died as a result of HIV infection that year. By 2015, protein and leads to a conformational change that produces these figures were 2.1 million newly infected and 1.1 million a fusion pore for viral entry. Productive replication and cell AIDS-related deaths. destruction does not occur until the Th cell is activated. In 2016, the UNAIDS global report stated that since 2014, Th cell activation is greatly enhanced not only in attempts 30% more people were receiving antiretroviral therapy (ART), to respond to HIV antigens, but also as a result of the which amounted to 17 million individuals. AIDS-related deaths secondary microbial infections seen in patients. Monocytes had reduced by 43% since 2003. The global coverage of ART and macrophages, Langerhans cells and follicular dendritic was 46% by the end of 2015, the largest gains were in east cells also express the CD4 molecule and are infected, but are 255 ERRNVPHGLFRVRUJ  22 CHAPTER Sexually transmitted infections absorption to receptor via gp120 chemokine receptor penetration at cell surface or uptake into vacuole CD4 fusion of viral envelope with cell membrane reverse via gp41 transcriptase double- stranded Figure 22.19 Electron micrograph showing HIV budding from the cell DNA ligation surface before release. (Courtesy of D. Hockley.) penetration integration infection is therefore affected by the levels of these chemokine host host provirus into host DNA co-receptors; for example, their expression may be up-regulated by opportunistic infections. transcription Productive infection of resting CD4 T cells in the single-stranded RNA (viral mRNA and progeny RNA) lymphoreticular system of the gastrointestinal tract occurs. These cells express integrin receptors, viral attachment translation molecules, as well as Th cell surface markers, and HIV-1 infection rapidly expands with a rise in HIV-1 RNA levels viral proteins at the same time as the irreversible depletion of reservoirs of Th cells as well as induction of an inflammatory cytokine and assembly chemokine response. A latency state is soon established with the formation of persistent lymphoid tissue viral reservoirs. nucleocapsid At first the immune system fights back against HIV infection, but then begins to fail During the first few months, virus-specific CD8-positive T cells are formed and reduce the viraemia, which is referred to as the HIV load. Innate and adaptive immune responses viral envelope to HIV infection lead to this set-point of HIV replication (Fig. proteins 22.22). This is followed by the appearance of neutralizing budding antibodies at around 3 months post-infection and viral escape release mutants develop. Up to 1010 infectious virus particles and up to 109 infected lymphocytes are produced daily. Then Figure 22.18 The HIV replication cycle. The virus enters the cell either the immune system begins to suffer gradual damage, and by fusion with the cell membrane at the cell surface or via uptake into a vacuole and release within the cell. the number of circulating CD4-positive T cells steadily falls and the HIV load rises. In addition to the loss of total CD4 T cells, T cell subsets change too including those involved in defence against bacteria. Nearly all infected CD4-positive not generally destroyed, potentially acting as a reservoir for T cells are in lymph nodes. The cell-mediated immune infection. Langerhans cells, for example dendritic cells in the responses to viral antigens, as judged by lymphoproliferation, skin and genital mucosa, may be the first cells infected. Later weaken, whereas responses to other antigens are normal. in the disease, there is a remarkable disruption of histological Perhaps the virus initially engineers a specific suppression pattern in lymphoid follicles as a result of the breakdown of of protective responses to itself. Eventually, the patient follicular dendritic cells. loses the battle to replace lost T cells, and the number falls HIV-1 enters host cells by binding the viral gp120 to the more rapidly. Skin test delayed-type hypersensitivity (DTH) CD4 receptor and a chemokine co-receptor on the host cell responses are absent, natural killer (NK) cell and cytotoxic surface. The CCR5 beta-chemokine receptor is important in T-cell (Tc) activity is reduced, and there are various other establishing the infection. Those people with CCR5 gene immunological abnormalities, including polyclonal activation deletions are resistant to infection. On the other hand, disease of B cells. Functional changes in T lymphocytes – reduced progression has been associated with HIV variants using responses to mitogens, reduced interleukin 2 (IL-2) and the CXCR4 alpha-chemokine receptor. Cell susceptibility to interferon gamma (IFNγ) production – are also seen. As 256 ERRNVPHGLFRVRUJ  Section Four Clinical manifestation and diagnosis of infections by body system Figure 22.20 Early spread of HIV infection (now worldwide). HIV-1 may have been present in central Africa for many years before increased migration and socioeconomic upheaval caused it to begin spreading in the late 1970s. Outside Africa, most infections occurred in men. mostly 1970s 1970s mostly late 1970s 1950s HIV-2 HIV-1 strains. Some are immune escape variants and others show increased pathogenicity. Before the advent of combined antiretroviral therapy the immunosuppression was permanent, the patient remained infectious, the virus persisted in the body and death was due to opportunist infections and tumours. HIV-2 appears to be transmitted less easily than HIV-1, probably because the viral load is lower, and the progression to AIDS is slower. HIV-2 is endemic in West Africa, and has spread to Portugal and parts of India. Routes of transmission In resource-rich countries, such as western and central Europe and North America, the main route of transmission is MSM. This is due to the higher risk of transmission by receptive anal Figure 22.21 Scanning electron micrograph of an HIV-infected Th cell intercourse, sex networks and risk taking increasing due to (×20 000). (Courtesy of D. Hockley.) effective ART. Infection is transmitted primarily from male to male and from male to female (Fig. 22.23), although not very efficiently compared with other STIs. Transmission from female to male, however, is a common and well-established AIDS develops, responses to HIV and unrelated antigens feature of HIV in Africa and Asia. are further depressed. The immune system has lost control. Plasma HIV-1 RNA load measurements have been shown to Heterosexual transmission has not so far predict clinical outcome and are used in clinical management been as important in resource-rich as in to help determine disease stage and progression as well as resource-poor countries antiretroviral therapy response. One explanation for the greater heterosexual spread in The following factors need to be considered in the resource-poor countries is that other STIs are more common, development of immune suppression: causing ulcers and discharges, which are sources of infected Th cells directly killed by virus lymphocytes and monocytes. Genital ulcers are associated Th cells induced to commit suicide (apoptosis, programmed with a fourfold increase in the risk of infection. Also, viral cell death) by virus strains from Asia and sub-Saharan Africa have been shown Th cells made vulnerable to immune attack by Tc cells to infect Langerhans cells in genital mucosa more easily than T-cell replenishment impaired by damage to the thymus do other strains. It is not clear whether HIV can infect males and lymph nodes and by infection of stem cells by the urethra or whether pre-existing genital skin breaks defects in antigen presentation associated with infection are necessary. As with other STIs, uncircumcised males are of dendritic cells more likely to be infected. immunosuppressive virus-coded molecules (gp120, gp41). A fall in plasma HIV load of 0.7 log10 is estimated to The host response is further handicapped by the high rate of reduce the risk of HIV transmission by 50%, which is why viral evolution assisted by the lack of a reverse transcriptase pre- and post-exposure prophylaxis preventative measures proofreading function. The virus exists as a quasispecies, in have been investigated and promoted, in conjunction with other words the infection comprises a number of heterogeneous safe sex messages. 257 ERRNVPHGLFRVRUJ  22 CHAPTER Sexually transmitted infections acute asymptomatic AIDS after ART 1200 106 106 CD4 lymphocyte count (cells per mm3) CD4 lymphocyte count (cells per mm3) HIV RNA copies per mL plasma HIV RNA copies per mL plasma HIV RNA HIV RNA 1000 CD4 blood CD4 blood 105 105 CD4 GIT CD4 GIT 800 500 104 104 600 103 103 400 normal 200 102 102 limit of detection of commercial assays 0 10 0 10 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 weeks years weeks years quasispecies diversity latently infected cells A C acute asymptomatic AIDS after ART normal 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 weeks years weeks years immune activation HIV-specific immune activation (eg ,LPS, sCD14) CD8 T cells (eg, LPS, sCD14, and HIV-specific T-cell activaton) HIV Ab CD4 T cells HIV Ab B D HIV-specific CD8 T cells Figure 22.22 A comparison of HIV infection untreated and after antiretroviral therapy. (A) If HIV infection is untreated CD4 T cells progressively decrease in blood and are rapidly depleted early on in the gastrointestinal tract. (B) The immediate result of HIV infection is the activation of the immune response including production of non-neutralizing antibodies and HIV-specific CD4 and CD8 T cells resulting in a temporal decrease in HIV RNA in blood. (C) Antiretroviral therapy significantly decreases HIV RNA with CD4 T cell recovery varying with the individual (panel). Conversely, there is reduced recovery of CD4 T cells in the gastrointestinal tract. (D) Antiretroviral therapy is associated with decreased HIV RNA and viral antigen and a decrease in HIV-specific T cells, although antibody persists in all patients. Immune activation also decreases but remains significantly increased in most patients compared with healthy controls. GIT, gastrointestinal tract; LPS, lipopolysaccharide. (From Maartens G., Celum C., Lewin S.R. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 2014; 384;258–271, Fig 3, with permission.) HIV can also be transmitted vertically from infected antiretroviral drug to both mother and child reduced HIV mothers to their babies, but the infant is not infected in 55–85% transmission by 47%. of pregnancies, the upper limit being associated with avoiding By the end of 2015, there were around 150 000 children breastfeeding. Overall, the infant is infected in about 20% of newly infected with HIV compared to 490 000 in 2000. 110 000 pregnancies in utero and intrapartum. The transmission rate children died from AIDS-related illnesses in 2015 compared peri- and postnatally is around 11–16%, the higher end of the to the estimated 320 000 who died in 2004. range depending on whether the child has been breastfed for Haemophiliacs and others who received contaminated up to 24 months. In resource-rich countries, antenatal HIV blood products were infected in the past. As with other screening, offering antiretroviral drugs during pregnancy blood-borne virus infections, using contaminated needles can and caesarean section delivery, avoiding breastfeeding, and lead to infection, i.e. in injecting drug use, tattooing, body giving antiretroviral drugs to the newborn infant have reduced piercing and acupuncture. the risk of HIV transmission to the child. In resource-poor Finally, healthcare workers are at risk of HIV infection after countries it has been shown that giving one dose of one sustaining needlestick or mucous membrane splash injuries 258 ERRNVPHGLFRVRUJ  Section Four Clinical manifestation and diagnosis of infections by body system Figure 22.23 Major routes of transmission of HIV. Although the heterosexual route of male male female transmission has so far been well established homo/bisexual heterosexual IVDU or received only in resource-poor countries, there is infected evidence that this route is becoming more blood/tissue important in the resource-rich countries. IVDU, intravenous drug user. male IVDU or received female infected heterosexual blood/tissue male child homosexual infected via in utero transmission major route of infection in resource-rich countries major route of infection in resource-poor countries involving an HIV-infected source. The risk of infection is (VZV), Toxoplasma gondii, JC virus (progressive multifocal approximately 1 in 400 and is dependent on a number of leukoencephalopathy, PML) and Cryptococcus neoformans. factors, including depth of the injury and amount of blood HIV exercises complex control over its own replication to which the recipient has been exposed. Wearing protective (see Fig. 22.18). Replication is also affected by responses to clothing such as gloves and goggles is part of universal other infections, which act as antigenic stimuli, and some of precautions to avoid exposure. them directly as transactivating agents. Some patients, especially in Africa, develop a wasting Clinical features disease (‘slim’ disease), possibly due to unknown intestinal Primary HIV infection may be accompanied by a mild infections or infestations, and perhaps also to the direct effects mononucleosis-type illness of the virus infecting cells of the intestinal wall. Signs and symptoms of the mild mononucleosis-type AIDS, symptomatic disease, consists of a large spectrum illness associated with HIV infection include fever, malaise, of microbial diseases acquired or reactivated as a result of maculopapular rash and lymphadenopathy. The acute infection the underlying immunosuppression due to HIV (Fig. 22.26; and rapid, widespread viral dissemination is followed by a Table 22.9). The disease picture of AIDS is therefore an indirect chronic asymptomatic stage. Viral replication is reduced in result of infection with HIV. line with the immune response, and the individual usually Before the advent of antiretroviral therapy, one study in remains well. The duration of this stage is dependent on New York reported a mortality rate of 80%, 5 years after a number of factors including the viral phenotype, host the onset of the disease, and the average survival time after immune response and use of antiretroviral therapy (Fig. hospital admission was 242 days. 22.24). Infected cells are, however, still present, and at a later stage the infected individual may develop weight loss, fever, Treatment persistent lymphadenopathy, oral candidiasis and diarrhoea. Antiretroviral therapy results in a dramatic Further viral replication takes place until finally, some years improvement in disease prognosis after initial infection, full-blown AIDS develops (Fig. 22.25). In the 1990s, a range of antiretroviral therapies was introduced which included the nucleoside reverse transcriptase inhibitors Progression to AIDS (NRTIs), non-nucleoside reverse transcriptase inhibitors Viral invasion of the CNS, with self-limiting aseptic (NNRTIs) and protease inhibitors (PIs). These were developed meningoencephalitis as the most common neurological picture, further over the next two decades in terms of new drugs in occurs in early infection. all classes and combinations. In 2003, a fusion inhibitor was A progressive HIV-associated encephalopathy is seen added to the list and by 2009 two other classes were available, in individuals with AIDS and is characterized by multiple an integrase inhibitor and chemokine receptor antagonist (see small nodules of inflammatory cells; most of the infected cells Ch. 34 for more detail). In combination with two NRTIs, the appear to be microglia or infiltrating macrophages. These NNRTI or PI drugs had a dramatic effect on progression cells express the CD4 antigen, and it has been suggested that to AIDS and the term highly active antiretroviral therapy infected monocytes carry the virus into the brain, but the (HAART) had changed by 2016 to combined antiretroviral picture is complicated by the various persistent infections therapy (cART). Side effects of the drugs include mitochondrial that are activated and give rise to their own CNS pathology. toxicity and altered fat distribution known as lipodystrophy. These include infections by HSV, varicella-zoster virus Treatment compliance was a problem because of the side 259 ERRNVPHGLFRVRUJ  22 CHAPTER Sexually transmitted infections Figure 22.24 Kinetics of immunological and Acute HIV syndrome virological events associated with human Wide dissemination of virus immunodeficiency (HIV) infection during acute Seeding of lymphoid tissues and early chronic phases. The schematic Destruction of gut-associated lymphoid tissue represents the sequence of events, including Establishment of HIV reservoirs the appearance of viral antigens, HIV-specific antibodies, and HIV-specific CD8+ T cells during Acute phase Early chronic phase the acute and early chronic phases of infection. 108 HIV reservoirs are established during the acute Plasma viraemia (copies of HIV RNA per mL) phase of infection soon after emergence of 107 plasma viraemia. Throughout the acute phase HIV-specific CD8+ T cells of infection, characterized by massive virus 106 replication and high levels of plasma viraemia, Viral escape from CD8+ T cells an acute HIV syndrome develops in the 5 10 Virus-specific neutralizing antibody majority of infected individuals, and the virus Viral escape from neutralizing antibody rapidly spreads to various lymphoid organs, 104 causing extensive depletion of CD4+ T cells. HIV-specific antibody+ (Western blot) Although anti-HIV immunity, including 103 HIV-specific antibody+/- (Western blot) virus-specific CD8+ T cells and antibodies, Viral set point HIV-specific antibody+ (ELISA) develops during the acute phase of infection, 102 HIV p24+ (ELISA) Limit of detection escaped viral mutants rapidly emerge. CD, 101 HIV RNA+ (PCR) cluster of differentiation; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain 100 reaction. (Redrawn from Moir, S., Chun T.W., 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Fauci A.S. Pathogenic mechanisms of HIV Days disease, Annu Rev Pathol Mech Dis 6:223–248, 2011.) effects and the number and frequency of pills taken each day. of samples tested in 2002, but had fallen to around 7% by Missing doses can lead to the development of drug resistance, 2013, from antiretroviral therapy naive adults infected with thus limiting treatment options. However, treatment has been HIV in the UK. This fall probably reflected the introduction simplified by not just combining individual classes of up to of improved combinations of ART, both in terms of drug three drugs in one tablet, but also combinations of classes classes as well as reduced pill burden improving compliance. (see Ch. 34). Improved monitoring using plasma HIV load The prevalence of drug-resistant viruses in newly infected measurements and CD4 counts and percentages has shown individuals will depend on factors such as changes in testing the success of cART, with rapid falls in plasma HIV load and guidance, more individuals virologically suppressed on cART rises in CD4 cells seen after initiating therapy. and whether the individual was infected by someone failing However, HIV can be detected in various compartments on antiretroviral therapy. Furthermore, a huge reduction was of the body including the CSF and genital tract. Antiretroviral seen in the prevalence of drug resistance mutations in ART drugs may not penetrate these sites, resulting in a high viral experienced individuals, from 72% in 2002 to 33% in 2013 load detectable in semen despite suppression of the plasma for reasons noted above. HIV load. Baseline antiretroviral drug resistance testing is part of As a result of improved diagnosis, surveillance, prevention the management guidelines in many countries before starting and use of cART, the number of AIDS-related deaths among treatment, as infection with a drug-resistant virus may affect children and adults worldwide had fallen from 1.5 million the efficacy of subsequent therapy. in 2010 to 1.1 million in 2015. Treatment of AIDS involves prophyla