Issue 4-2003-

Sexually-Transmitted Viral Diseases in Women: Clinical and Epidemiological
Aspects and Advances in Laboratory Diagnosis
Álvaro Piazzetta Pinto1, Hugo César Cardoso Baggio2
Pathology Department1 and Radiology Department2, and Guilherme Barroso Guedes3
Teaching Hospital of the Federal University of Paraná3;School of Medicine, Federal University of Paraná;Curitiba, PR, Brazil Sexually transmitted diseases (STDs) have long been known, but they have only recently been
recognized as causes of significant long-term morbidity, mainly as a result of increased knowledge
concerning viral STDs. The relationship of these diseases with conditions such as anogenital
cancer and acquired immunodeficiency syndrome (AIDS) has made viral STDs an important
issue in the healthcare of women and infants, and in reproductive health. The evolution of the
AIDS pandemic is now characterized by growing differences between rich and poor nations. New
diagnostic tools include rapid tests of blood, urine and saliva samples. New techniques, such as
computerized cytology, have been developed for the diagnosis of human papillomavirus (HPV).
Women infected with HIV are at a greater risk of being co-infected with HPV, and they are also
more prone to the progression and persistence of HPV lesions. The herpes simplex virus presents
high rates of co-infection with HIV, and it plays a particularly important role in increasing
transmission rates of this virus.
Key Words: Sexually-transmitted diseases, viral; HIV; human papillomavirus; herpes simplex virus.
Sexually transmitted diseases (STDs) have long been as well as reproductive health. The medical diagnosis known to cause acute pathological syndromes, such of STDs, AIDS, and genital cancer is currently a as genital secretion and ulceration. However, they only fundamental element of women’s healthcare [1].
recently have come to be considered significant causes Our capacity to diagnose STDs increased following of long-term morbidity. This is principally due to the the introduction of tests based on the amplification of large amount of information that has been collected nucleic acids. These tests were initially developed for over the past 20 years on a group of agents that cause the diagnosis of viral STDs and are particularly useful these diseases: the viruses. After the association between for this purpose. They present high sensitivity, and they virus and anogenital cancer was established, and permit the use of non-invasive specimens, such as urine following the emergence of the first cases of Acquired and vaginal tissue, self-collected by the patients.
Immunodeficiency Syndrome (AIDS), viral STDs Although the number of false results obtained with this began to be recognized as important diseases that technology has been low, there has been some influence the health of women and breastfeeding infants, reluctance to substitute traditional methods for this new Received on 15 December 2004; revised 19 June 2005.
methodology. One negative aspect is the high cost [2].
Address for correspondence: Dr. Álvaro Piazzetta Pinto.
Our objective was to identify and describe the principal Departamento de Patologia, Hospital de Clínicas, Universidade viral STDs, and to examine epidemiological factors and Federal do Paraná. Rua General Carneiro 181, Curitiba, PR, the relationship that exists between the different viruses.
Brazil. Zip code: 80069-900. E-mail: [email protected].
Finally, we examined the diagnostic methods Telephone: (55 41) 224 79 88 / FAX: (55 41) 324 46 84.
traditionally used for their detection, as well as more The Brazilian Journal of Infectious Diseases 2005;9(3):241-250
2005 by The Brazilian Journal of Infectious Diseases and Among the many sexually transmitted diseases Contexto Publishing. All rights reserved.
caused by viruses, the principal STDs are AIDS (human Sexually-Transmitted Viral Diseases in Women immunodeficiency virus – HIV), genital warts, population [6]; b) a spontaneous change in behavior in intraepithelial lesions and genital squamous cell certain segments of the population [6]; c) the impact of carcinomas (human papillomavirus – HPV), and herpes different prevention initiatives by governmental and non- (herpes simplex virus – HSV-2 and HSV-1) (Table governmental organizations, and d) the use of HAART, which is readily available in our country [7].
Nevertheless, this relative deceleration of the spread Acquired Immunodeficiency Syndrome (AIDS)
of the epidemic is not homogenous, both with respectto the different geographical regions of the country and Almost 50 million people worldwide have been to the affected segments of the population [8]. The infected by HIV, and 12-13 million children have been speed of expansion has decreased among men in large made orphans by AIDS. Twenty years after its cities and in the southeast part of the country [9]. More discovery, the HIV pandemic continues to evolve in recently, an increase has been seen in south Brazil, not magnitude and diversity, and it is currently a global public only in the rate of AIDS cases registered but also in the health problem [3,4]. The distribution of AIDS cases number of cases resulting from heterosexual is characterized by a widening gap between the rich transmission. There has been dissemination of the nations of North America and Europe and the poor epidemic from the large urban centers to the rural areas nations of Africa, Asia and Latin America [3]. An [10]. The AIDS epidemic in Brazil began among important reduction in the number of new cases, individuals of highly educated social groups and morbidity and mortality from AIDS has been seen in continuously progressed to lower socioeconomic level the US and Western Europe, as a result of the use of groups [11]. Irrespective of the focus, one constant high-cost, intensive therapies, principally HAART finding of such studies is that certain segments of the (highly active antiretroviral therapy). However, new population, such as injectable-drug users and HIV infections continue to occur every year at a constant women, continue to be disproportionately affected rate in these same countries. Moreover, there is by the epidemic [8,10,11]. Women also tend to die evidence of an increase in high-risk behavior in certain younger than men; this hold true in all regions of the populations, indicating failure in primary prevention.
However, the vast majority of new infections still occur Women are the segment of the AIDS population in developing countries. While the two giants, India and with the fastest growth rate. Maternal-fetal transmission China, are beginning to provide Asia’s ultimate and the high mortality and morbidity of the disease in contribution to the pandemic, the situation in Africa is children are additional reasons for strengthening efforts the most desperate, with epidemics rapidly growing in to combat AIDS in women. When the virus is various countries in the south and eastern parts of the diagnosed in pregnant patients, treatment (zidovudine) continent, affecting all levels of African society. In these reduces the risk of maternal-fetal transmission by two- countries, expansion of the epidemic is not decreasing, thirds [13]. Diagnosis is generally made late, since the and there are devastating effects on communities, first signs and symptoms of the disease are subtle. They families and individuals [4]. The development of a include vaginal infections, abnormal cervical/vaginal vaccine, seen as an essential step towards control of cytology examinations, and other STDs with unusual the epidemic, is complicated by the genetic diversity of clinical courses that are severe, recurrent or resistant the virus and the inability of the immune system to to treatment [14]. The traditional diagnosis, which includes serological screening by enzymatic In Brazil, AIDS, and its associated diseases, have immunoassay (ELISA), is followed by a second spread more slowly in recent years [5]. This is probably confirmatory ELISA. A more specific, definitive due to a combination of factors: a) saturation of the diagnosis is reached using the Western Blotting higher risk segments, i.e. relative lack of a susceptible Sexually-Transmitted Viral Diseases in Women Table 1. Virology of the principal agents of viral STDS
Virus Family
Genetic material
Size of virion
Target cells
Monocytes / macrophagesMicroglia / MGC of SNCLangerhan’s cells HIV: human immunodeficiency virus; HPV: human papilloma virus; HSV: herpes simplex virus; DNA: desoxyribonucleicacid; RNA: ribonucleic acid; MGC: multinuclear giant cells; SNC: central nervous system.
immunofluorescence assay (IFA) has also been found Viral load tests and genotyping are used to select to be efficient as a definitive test [15]. While ELISA and evaluate therapeutic options. The use of these tests measures antibodies against one or more proteins of and other viral detection tests for diagnosis should be the viral envelope, and can give false-positive results, limited to situations in which serology is not definitive, Western Blot measures the presence of antibodies such as in cases of neonatal infection or acute HIV against each of the viral antigens, including the core infection, since these tests are less accurate than protein (p24). Together, the serological tests have a >99.3% sensitivity andt99.7% specificity [16].
When rapid AIDS tests first began to be used in the 1980s, and at the beginning of the 90s [17], theyprovoked much controversy [18-21]. In more recent Genital warts, or condylomata acuminate (clinical times, the debate has been renewed [22]. Rapid testing form of the disease), are small papillary projections and self-testing have become widespread in some that generally occur on the vulva or in the vagina. They countries such as the US [23] and have been banned are caused by the human papillomavirus (HPV), a highly in others, such as Germany [24]. These tests include infectious agent. Many individuals exposed to HPV the detection of antibodies in drops of blood, urine [23] develop flat lesions (subclinical form of the disease) instead of visible warts. These lesions most often affect Rapid testing has a high sensitivity and is sufficient the cervix, are called intraepithelial lesions and are to confirm the absence of infection outside the considered precursors of squamous cell carcinoma.
immunological window period. Its specificity is t 98.9% More commonly, the genetic viral material installs itself and requires supplementary serological testing to in the mucosa, and it remains there for years without confirm diagnosis [29-31]. These tests are extremely causing any lesion (latent form of the disease).
useful in situations requiring fast detection of infection, HPV is a circular, double-stranded DNA virus of such as following occupational exposure.
the Papovaviridae family, with approximately 8,000 Saliva testing uses the same antibody detection base pairs. More than 70 types of HPV have been methods as serological testing (ELISA, Western Blot).
identified. Among these, approximately 30 affect the The agreement of results is quite high, permitting this genital mucosa, are transmitted sexually and are related method to be used as an alternative to serology [25].
to the above-mentioned lesions. Types 6, 11, 42, 43 Sexually-Transmitted Viral Diseases in Women and 44 cause low risk lesions for malignancy, while substituting cytotechnicians for computers [49]. Finally, types 16, 18, 45 and 56 are associated with high-risk following a trend currently observed with other STDS, lesions and are also referred to as oncogenic.
a study has reported adequately sensitive HPV Nevertheless, the mere presence of a high-risk form of molecular detection in self-collected vaginal, vulvar and HPV is not in itself sufficient to trigger the carcinogenic urine samples [50]. We found a sensitivity of from 45 process. Co-factors, such as immunosuppression, to 86% and a specificity of 54% to 70% in self- tabagism, micro-traumas, nutritional and hormonal collected samples, compared to 98% sensitivity and factors, number of sexual partners and a history of 52% specificity with physician-collected cervical infections (vaginosis, herpes simplex, etc.) have to be present [33]. The progression and natural course ofcervical disease are still not fully understood [34].
The Papanicolaou test is a morphological screening method for viral infections and its consequent Systemic and local cellular immunity are factors of intraepithelial lesions [35]. Colposcopy permits extreme importance in HPV infection and its visualization of the lesions and histopathology allows a manifestations [51]. In fact, immunosuppressed women definitive diagnosis to be made. Techniques for the have a high risk of developing intraepithelial and invasive amplification and hybridization of nucleic acids have squamous cell neoplasia of the lower genital tract [33].
been used since 1980 for the detection, typing and This group includes patients who have been submitted quantification of viral load [36]. Indications for their to organ transplant, patients with Hodgkin’s disease, use include low-grade squamous intraepithelial lesions those being treated with immunosuppressive therapy (LGSIL), which in 30% of cases are associated with in general, and HIV-positive women [33].
oncogenic types of HPV, and lesions that are difficult The HIV-HPV interaction is particularly important, to characterize by cytology (ASCUS – atypical since the two viruses are sexually transmitted, placing squamous cells of undetermined significance) [37].
high-risk populations in contact, making co-infection Although molecular biology techniques, such as common [33]. A study carried out in São Paulo showed polymerase chain reaction (PCR) [38-40] and hybrid a high prevalence of high-risk HPV infection (34.8%) capture (HC) [41-43], present high sensitivity and and of high-grade intraepithelial lesions. Two or more specificity for HPV detection and are frequently used subtypes of HPV were found in 45% of the patients as quality controls for the other techniques, the use of [52]. Case-control studies have shown HIV infection these methods for screening purposes is still not to be an independent risk factor for HPV, both in its accepted. The high cost and the small increase in latent and clinical forms [33]. These results reinforce sensitivity gained when this method is added to cytology the need for regular gynecological follow-up of HIV- are the principal justifications for not using molecular positive patients to ensure early diagnosis of preinvasive methods as a screening tool [44-47]. Other adjuvant lesions and for the prevention of cervical cancer.
methods of cytology are being developed and improved Invasive cervical cancer and its precursors are the in parallel with these methods; however their most important gynecological manifestation of HIV development has been less emphasized. Such methods infection [53]. Infection by this virus is related to an include macroscopic inspection of the cervix, increase in prevalence (2-3 times greater) and cervicography and colposcopy [48]. Liquid phase persistence (7 times greater) of HPV infection.
cytology has led to an improvement in the quality of Persistence of HPV infection is known to be important the material collected and has offered the possibility of in the development and progression of cervical associating cytological and molecular methods in the intraepithelial lesions, and this is one of the factors that same sample. Meanwhile, computerized cytology has may explain the higher occurrence rate of these lesions improved the quality of cytological scrutiny by in HIV-positive patients [54-59]. HIV-positive women Sexually-Transmitted Viral Diseases in Women have a 3-5 times greater risk of developing intraepithelial detected in approximately 15% of herpetic genital lesions [53,57,60] and a 3-4.5 times greater risk of infections. Since the seventies, the prevalence of HSV- developing invasive neoplasia [53,60]. In a study carried 2 infection has been steadily increasing; this problem out by Ellerbrock [53], 328 HIV-positive women and has become a public health issue in recent years, even 325 HIV-negative women, followed up for a mean of during the “HIV decade” [62]. One recent study on 30 months, 20% of the HIV-positive women and 5% the prevalence of HSV-2 infection in middle-aged of the HIV-negative women developed intraepithelial Brazilian women found 42% seropositivity [63].
Carvalho et al. [64] found varying prevalence rates Various studies have shown that HIV-positive according to the subpopulation studied: 6.9% of patients with low CD + lymphocyte counts have greater students evaluated, 22.6% of pregnant women and viral loads (copy count twice as high for patients with 53.1% of the individuals with sexually transmitted CD + < 200 cells/PL) [33,61] and a greater persistence diseases presented antibodies to HSV-2. They also of HPV infection [54], as well as a higher prevalence reported low occurrence of recognized symptoms in of low, intermediate, and high-grade cervical intraepithelial lesions [55,58,61]. The prevalence of Primary infection with HSV-2 lasts around three persistent infection by subtypes of high grade HPV also weeks, and during this period the virus is released from appears to be significantly greater in HIV-positive the lesions [65]. This infection may be asymptomatic or mild; it presents systemic symptoms in around 70% Studies have shown that co-infection with HIV is of cases, pain and localized pruritus in 98%, dysuria in also a risk factor for the other neoplasias for which 63%, and painful lymphadenopathy in 80% [66].
HPV is a co-factor. According to a study carried out Locally, the infection appears in the form of painful by Frisch [60], HIV-positive patients have a greater mucocutaneous, vesicular and ulcerative lesions, relative risk of developing intraepithelial lesions of the situated on the outer genitalia or cervix [65,66]. This vulva and vagina (RR 3.9), anus (RR 7.8 for women clinical condition and the resulting complications tend and 60.1 for men) and penis (RR 6.9). Similar results to be more severe in women, in whom they are were found for invasive neoplasias of the vulva and frequently associated with unbearable pain [65].
vagina (RR 5.8), anal canal (RR 6.8 in women and Complications arising from the primary infection include 37.9 in men), penis (RR 3.7), tonsils (RR 2.6) and aseptic meningitis (in up to 25% of women), sacral radiculomyelitis and neuralgias [65]. According to a It is still not clear whether the HIV-HPV interaction study carried out by Lafferty, the recurrence rate of is related directly or indirectly to the immunosuppression genital infections caused by HSV-2 is 33% per month, caused by HIV. Co-infection does not occur in the in contrast with 0.1% recurrence in the case of orolabial cervix; however, molecular interactions do occur between the two viruses. They are therefore probably Recurring episodes are milder and of shorter caused by extracellular factors [33]. The increase in duration (7-10 days) than the first infection and are HPV gene expression in HIV-positive women may be characterized by the presence of vesicular and due to interactions involving the HIV-1-trans-activating ulcerative lesions on an erythematous base, or by local (Tat-1) protein and the p97 HPV 16 promoter protein, irritation only. The virus is released from these lesions leading to reversal of HPV E2 gene repression [33].
The virus is most frequently transmitted by symptomatic patients but transmission may also occur insymptomless patients [68]. Two other factors aggravate The herpes simplex-2 virus (HSV-2) is a the control of the disease: the facts that antiviral therapy predominantly genital pathogen; while HSV-1 is does not completely eliminate the virus and that condoms Sexually-Transmitted Viral Diseases in Women are not totally effective in prevention since the herpes virus frequently affects the outer genitalia.
Cytopathology of exfoliated cells may permit The prevalence of HSV infection is considerably diagnosis, but this depends on adequate sample higher in HIV-positive patients. Santos et al. found collection and the evolutive phase of the lesion. General 73% positivity for HSV-2 in serological testing of HIV- sensitivity of this method is around 60-70% [65].
positive patients in Brazil [77], a finding that is similar Enzymatic serological tests for HSV antibodies to data from studies carried out in other countries [78- (ELISA) have been available for many years, but they 80]. These data reflect the behavioral risk factors present low sensitivity and specificity and have common to infection by the two viruses.
traditionally rarely been used to define treatment of According to various studies, genital ulceration, of infected patients. The time required for serological which HSV is the most common cause, is an important diagnosis is longer than that available for the initiation risk factor for the acquisition and transmission of HIV of treatment [65]. The definitive epidemiological test and contributes towards the dissemination of this virus has been the Western Blot; however, this is generally [77,81-85]. Telzak et al. reported that patients with only available in research institutes and is very expensive genital ulceration have a three-fold greater risk of [69]. Recently, new serological tests for specific acquiring HIV than a similar population without antibodies for HSV-1 and HSV-2 have become ulceration [86]. A study carried out by Latif et al. in commercially available [70-72]. These tests have made Zimbabwe in serodiscordant couples (only one member it possible to identify the infection in symptomatic as of the couple was HIV-positive) showed that the HIV- well as in asymptomatic patients [73].
negative partners of HIV-positive individuals who had Cultures positive for HSV from the contents of genital ulceration had a five-fold greater risk of the vesicula or the edges of the ulcers is considered acquiring HIV than did HIV-negative partners of the traditional definitive diagnostic method. However, individuals with no ulceration [87].
diagnosis by this method requires 7-28 days and has The explanation of how genital herpes serves as a been shown to underestimate the number of patients co-factor in HIV contagion does not appear to be infected. The sensitivity of this method is around 50% limited to the simple idea of continuity determined by and is higher during the primary infection than during the herpetic infection that would serve as an entry or recurring episodes. During recurrences, samples exit route for HIV. There is evidence supporting an should preferentially be collected in the vesicular increase in HIV expression in the mucosa during phase, not when lesions are crusted [74]. Moreover, reactivation of HSV [88]. The migration of CD + most patients who are seropositive according to lymphocytes to the infection site may be one of the Western Blot are unaware of their symptoms factors responsible [89]. Activation of these (unrecognized infection), or they present subclinical lymphocytes previously infected by HIV leads to a infection and do not undergo culture [69]. Diagnostic greater replication of the former virus in response to technology examining nucleic acids has also proved the HSV infection [90]. During reactivation, as well as to be viable for the detection and typing of HSV and stimulating the CD + lymphocytes, some HSV proteins may be able to substitute culture as the definitive seem to trans-activate the long terminal repeat of HIV, method [75,76]. The molecular method presents an increasing replication [91-92]. In a study by Schacker increase in sensitivity of up to 30% compared to et al., HIV RNA was detected in 25/26 episodes of standard virological methods (detection of antigen by HSV reactivation, in independent titers of the HIV immunofluorescence followed by isolation and culture) plasmatic viral load [90]. According to Heng et al., the [76], but it has still not been proven to be cost- HSV infection enabled replication of HIV in the effective, except for the detection of the virus in spinal keratinocytes, which are cells normally not infected by fluid, for which it is the method of choice [65].
HIV because of the absence of CD markers on their Sexually-Transmitted Viral Diseases in Women surface [93]. In this same study, potentialization of the de Oliveira for her support in organizing data for replication of HSV in the presence of HIV was seen.
this manuscript. This study was carried out at the These findings, taken together, may explain the Pathology Department of the Teaching Hospital, greater risk of HIV transmission in patients co-infected Federal University of Paraná, Curitiba, PR, Brazil.
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