Abstract

The present review investigates the association between the presence of urological disorders and the transmission of human immunodeficiency virus (HIV). This study suggests that sexually transmitted infections (STIs) can increase the risk of infecting sexual partner or being infected with HIV. However, community-based STI control was not proved to be an effective HIV prevention strategy, although a few clinical trials revealed the possibility that aggressive treatment of STIs could decrease the transmission of HIV in specific population groups. Since the introduction of highly active antiretroviral therapy (HAART), HIV infection has become a chronic disease. Antiretroviral medications also were shown to be effective for the pre-exposure and post-exposure prophylaxis of HIV infection. Urologists should perform a critical role in preventing transmission of HIV by screening of HIV in the patients with urological disorders and using effective strategies to control the HIV epidemic.

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Summary of recommendation

1. There is no definite evidence to prove that community- or population-based sexually transmitted infection (STI) control is an effective HIV prevention strategy (LoE 1a).
2. Immediate diagnostic evaluation and appropriate treatment of an individual with any symptomatic sexually transmitted infections (STIs) can reduce the risk of HIV acquisition (GoR B).
3. Prompt and effective treatment of HIV-infected individuals experiencing genital symptoms can limit the transmission of HIV (GoR B).
4. Male circumcision can be recommended for HIV prevention in men (LoE 1a; GoR A).
5. Interventions targeting people living with HIV are efficacious in reducing unprotected sex and acquisition of STIs (GoR B).
6. Short-term antiretroviral treatments, such as preexposure and postexposure chemoprophylaxis, are proved to reduce the risk of HIV transmission after exposure to HIV (LoE 1a; GoR A).

1 Introduction

Acquired immunodeficiency syndrome (AIDS) is an immune system disorder caused by human immunodeficiency virus (HIV) infection, and characterized by the development of various opportunistic infections, neoplasms, or other severe life-threatening conditions.

AIDS was a rapidly progressive and fatal disease in the early 1980s, however, the introduction of highly active antiretroviral therapy (HAART) in the Western world has dramatically improved survival and the quality of life for the HIV-positive patient, although AIDS remains the leading cause of death in many African cities [1], [2], [3], [4].

The three main modes of HIV transmission have changed little: unprotected intercourse, contact with blood, and transmission from mother to child [3]. Among them, HIV acquired through unprotected heterosexual intercourse is on the rise and considered to be a urological factor for HIV transmission. This review evaluates the scientific evidence suggesting that urological factors increase the efficiency of HIV transmission and discusses the important urological manifestations of HIV infection.

2 Methods

A systematic literature search and review of existing scientific evidence published in peer reviewed journals was performed in MEDLINE/PubMed for the period from 1 January 1986 to 31 December 2015 with the following key words: HIV transmission, sexually transmitted infection; and the following limitations: human, clinical trials, randomized controlled trials (RCTs), systemic review, meta-analysis, English. By the literature search and review, 2,223 articles were found and screened by the title and abstract of each electronic citation. We included clinical trials or review articles in which primary or secondary outcomes were HIV incidence or revealed risk of HIV transmission after any intervention for biomedical STI control. After clearly irrelevant articles were removed, 21 articles were obtained for full-text scrutiny. References from retrieved study reports and reviews were also screened for additional studies.

The studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using European Association of Urology (EAU) guidelines 2015 and ICUD standards (for details see Preface) [5], [6].

3 Epidemiology of HIV/AIDS

There were 36.9 million (34.3 million–41.4 million) people living with HIV in 2014. Since 2000, 38.1 million people have become infected with HIV and 25.3 million people have died of AIDS-related illnesses. Although the global percentage of people living with HIV has stabilized since 2000, the overall number of people living with HIV has increased as a result of ongoing number of new infections each year and the beneficial effects of highly active antiretroviral therapy (HAART). New HIV infections have fallen by 35% since 2000. The annual number of new HIV infections decreased from 3.1 million (3.0 million–3.3 million) in 2000 to 2.0 million (1.9 million–2.2 million) in 2014. The rate of new HIV infections has decreased globally, however, the number of new HIV infections in Middle East, North Africa, Eastern Europe, and Central Asia increased. Global efforts should be continued to prevent HIV transmission all over the world [2].

4 Dynamics of HIV transmission

Although HIV can be transmitted from person to person through HIV-infected blood, semen, vaginal fluids, and breast milk, sexual intercourse is the most common mode of HIV transmission. Sexual transmission accounts for 75 to 85 percent of HIV transmission [3], [4] and the risk of male to female transmission is much higher than that of female to male transmission [7], [8], [9]. The risk of female-to-male HIV transmission per episode of vaginal intercourse was estimated to be one in 700 to one in 3,000. In addition, the risk of male-to-female HIV transmission was estimated to be one in 200 to one in 2,000. The probability of HIV transmission per one episode of needle sharing with HIV-infected person was 0.67 percent (one in 150) [3].

Risk of HIV transmission varies depending on many systemic factors as well as local urogenital factors [3], [4], [7]. Differences in HIV infectiousness, host susceptibility, or differences in sexual behaviors can affect the spread of HIV infection. Factors that increase the concentration of HIV in genital tract secretions and in the blood may enhance the infectiousness of the HIV. As the viral loads of HIV-infected persons change according to the different stages of disease, the risk of HIV transmission is enhanced in primary infection or in later stages of HIV disease when the concentration of HIV is increased. It was known that the risk of HIV transmission was the greatest in people with acute HIV infection [3]. In a Ugandan population-based cohort, the adjusted rate ratio of HIV transmission per coital act was estimated by multivariate Poisson regression. The average rates of HIV transmission were 0.0082 and 0.0015/coital act within ~2.5 months and 6–15 months after seroconversion of the index partner, respectively [10]. In addition, the rate of HIV transmission 6–25 months before the death of the index partner was estimated to be 0.0028/coital act. As a result, early- and late-stage infection, higher HIV load, genital ulcer disease, and younger age of the index partner were shown to be significantly associated with higher rates of HIV transmission [10]. Furthermore, semen HIV viral burden influence on heterosexual transmission. It was known that sexual transmission was unlikely to occur, at one per 10,000 episodes of intercourse, when HIV RNA in semen was low (<5,000 copies/mL) [11]. On the other hand, when the concentration of HIV in semen was above 1,000,000 copies/mL, the probability of HIV transmission were estimated to rise to three per 100 episodes of intercourse. Viral levels in the female genital tract and in semen correlate with systemic viral loads [12], [13], [14], although women may have detectable genital tract HIV-1 viral load even when their plasma HIV-1 RNA level is undetectable after receiving antiretroviral therapy. It is known that women with below detectable plasma HIV-1 RNA level may have less risk of HIV sexual transmission on a population level, but may continue to be possibly infectious on an individual level [15]. In fact, one of the most important determinants of genital viral loads is the presence of STIs [16], [17], [18]. It was also known that the concentrations of HIV in genital tract secretions from males and females were increased in patients with sexually transmitted infections (STIs) as well as in patients with acute HIV infection or the later stages of HIV infection [19], [20], [21], [22], [23]. In female patients with HIV infection, herpes simplex virus (HSV), human papillomavirus (HPV), Chlamydia trachomatis, Neisseria gonorrhoeae, Candida, genital ulceration, bacterial vaginosis (BV) and vaginal discharge have been associated with increased HIV shedding [18]. In male patients with HIV infection, it was also reported that Trichomonas vaginalis, Neisseria gonorrhoeae, cytomegalovirus (CMV), genital ulcer and urethritis were linked to HIV shedding in semen [18]. The dynamics of HIV infection can be influenced by the genetic characteristics of HIV-1. The biological characteristics of HIV-1 that are different for various HIV-1 subtypes may influence infectivity and transmissibility, the rate of disease progression, and the response to antiretroviral therapy (ART). Several research papers reported that the particular viral clade and circulating recombinant form (CRF) were found in some limited areas or limited population group with specific transmission pattern [24], [25], [26]. Several kinds of HIV-1 transmission routes associated with diverse risk behaviors have been noted in different regions of the world, and additionally it was reported that the HIV-1 epidemic in each region was caused by different subtypes [25]. In Thailand, the cocirculation of subtype B among intravenous drug users (IDUs) and CRF01_AE among heterosexuals was reported [27]. In South Africa, the segregation of subtype B to homosexuals and subtype C to heterosexuals was reported [28]. In Argentina, two concurrent epidemics have been reported, one among heterosexual men and women, is dominated by env subtype F, and the other among men who have sex with men, dominated by env subtype B [29]. Although the subtype B was the prevalent type in Europe, the progressive decrease in the transmission rate among IDUs and men who have sex with men and the parallel increase in heterosexual transmission introduced variants of non-B subtype into the Italian HIV-1 epidemic, which was also noted in other Western European countries [30], [31]. While the traditional risk groups such as homosexuals had high level of knowledge and avoided high-risk practices, the heterosexuals did not fully understand the importance of avoiding the HIV-related risk behaviors. Therefore, the increase in heterosexual transmission of HIV-1 between European partners and immigrants from non-Western countries, where non-B clades and CRFs were prevalent, introduced HIV-1 variants of non-B subtype in the Italian epidemic [31]. It was reported that the introduction and spread of different HIV-1 clade or recombinant viruses associated with the change of transmission pattern might influence the disease progression and the evolution of the HIV/AIDS epidemic [32].

5 Relative risk for specific exposure

Evidence studies for STIs as a risk factor of HIV transmission are summarized in table 1. Classic sexually transmitted diseases (STDs) (genital ulcers and mucosal inflammatory diseases) occur in the same geographic areas as HIV, and compelling epidemiological evidence supports the view that such diseases increase HIV transmission; indeed, the interaction between classic STDs and HIV is referred to as “epidemiological synergy” [16]. Several large RCTs were undertaken to investigate whether controlling STIs can reduce the incidence of HIV in a community. The first RCT enrolled 12,537 adults aged 15–54 years from six intervention communities and six pair-matched comparisons [33]. Baseline HIV prevalence was 3.8% and 4.4% in the intervention and control communities, respectively. There was a reduction in syphilis and symptomatic urethritis in the intervention group. The incidence of HIV infection was 1.2% and 1.9% in the intervention and control groups, respectively (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.42–0.70), corresponding to a 38% reduction (95% CI 15–55%) in the intervention group. The intervention reduced both the incidence/prevalence of STIs and the incidence of HIV infection. Since then, other trials in Rakai [34], [35] and Masaka [36] showed that there was no significant effect of STDs control on HIV prevention. Possible hypotheses have been suggested to explain these contrasting results. The relative contribution of individual STIs to an epidemic varies at different times and places depending on the maturity of the epidemic and the relative prevalence of HIV and STI infection in the community [37]. Although they did not show a reductions in HIV acquisition, there were reductions in adverse other outcomes such as neonatal mortality. A cluster-randomized trial in Zimbabwe also showed that STI management did not reduce population-level HIV-1 incidence in a declining epidemic [38]. In systemic review of Cochrane Database, no evidences were found proving that control of STIs could reduce HIV incidence at the population or community level [39]. In addition, Gray and Wawer expressed concern that the policy to control STIs as a general HIV-prevention strategy might waste scarse resources which could be used for the other proven efficacious interventions [40]. However, O'Farrell suggested the possibility that relaxation of STI control could lead to increased STI rates and enhanced HIV transmission [41].

Table 1: Evidence table for studies of sexually transmitted infections (STIs) as risk factor of both HIV transmission and acquisition that include original data, systematic reviews, meta-analysis, or other human data (1986–2015).

Study type	STI type	Leader author, year, reference	Design	Level of Evidence (LoE) Positive (role of a risk factor) or Negative
Systematic reviews, meta-analysis and modeling
	STIs	Sangani, 2004 [121]	Systematic review and meta-analysis of the five RCTs	1, Positive
	STIs	Hay, 2008 [37]	Systematic reviews	1, Positive
	STIs	Ng, 2011 [122]	Sytematic review and meta-analysis of the four RCTs	1, Negative
	Bacterial vaginosis	Atashili, 2008 [123]	Systematic review and meta-analysis of the 23 eligible publications	2, Positive
Randomized-controlled trials
	STIs	Grosskurth, 1995 [33]	12,537 adults aged 15–54 in six intervention communities and six pair-matched comparisons communities in Mwanza, Tanzania	1, Positive
	STIs	Wawer, 1999 [34]	12,726 adults aged 15–59 in Rakai, rural Uganda	1, Negative
	STIs	Gray, 2001 [35]	2,070 pregnant women in Rakai, Uganda	1, Negative
	STIs	Kamali, 2003 [36]	12,819 individuals aged 13 and older in Masaka, rural Uganda	1, Negative
	STIs	Gregson, 2007 [38]	11,980 individuals in Zimbabwe	1, Negative
	CMV	Casper, 2008 [51]	16 HIV-positive men and 10 HIV-negative men in Seattle, USA	1, Positive
Non-randomized cohort studies
	Genital ulcers	Cameron, 1989 [124]	Prospective study of 422 men who had acquired STD from female CSWs in Nairobi	2, Positive
	Genital ulcers, Chlamydia trachomatis	Plummer, 1991 [125]	124 seronegative female CSWs in Nairobi	2, Positive
	Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis	Laga, 1995 [126]	Cohort study of 431 HIV-negative female CSWs in Kinshasa, Zaire followed for 2 years	2, Positive
	Bacterial vaginosis	Taha, 1998 [127]	1,296 antenatal pregnant and 1,169 postnatal seronegative women in Malawi	2, Positive
	Bacterial vaginosis	Martin, 1999 [128]	657 seronegative female CSWs in Kenya	2, Positive
	Bacterial vaginosis	Myer, 2005 [129]	410 women screened for cervical cancer in South Africa	2, Positive
	CMV	Sheth, 2006 [49]	26 HIV-infected MSMs and 15 uninfected controls (6 MSMs; 9 heterosexuals) in Toronto, Canada	2, Positive
	HSV-2	Rebbapragada, 2007 [44]	55 HIV-infected and 36 uninfected female CSWs in Nairobi, Kenya	2, Positive
Case-control studies
	Urethritis	Cohen, 1997 [130]	135 HIV-1-seropositive men in Malawi	3, Positive
	Neisseria gonorrhoeae, Chlamydia trachomatis, genital ulcers	Ghys, 1997 [131]	609 HIV-1-seropositive women in Abidjan, Cote d'Ivoire	3, Positive
Case-series
	HSV, syphilis	Stamm, 1988 [132]	200 homosexual men with acute proctitis and 111 asymptomatic homosexuals	3, Positive
The hierarchy of study types was: systematic reviews and meta-analysis of randomized controlled trials, non-randomized cohort studies, case-control studies, case series, and expert opinion (as the lowest level).

In Burkina Faso, a randomized, double-blind, placebo-controlled trial of herpes simplex virus (HSV) suppressive therapy with valacyclovir was undertaken among women who were seropositive for HIV-1 and HSV-2 [42]. All were ineligible for highly active antiretroviral therapy and followed for 24 weeks with 12 weeks before and 12 weeks after randomization. Valacyclovir therapy was found to be associated with a significant decrease in the frequency of genital HIV-1 RNA (OR 0.41, 95% CI 0.21–0.80) and in the mean quantity of the virus (log10 copies per milliliter -0.29, 95% CI -0.44–-0.15). Genital herpes infection is now thought to be the most important cofactor in mature epidemics of HIV [37]. HSV-2 was known to drive secondary transmission of HIV from HSV2-HIV co-infected persons [43]. Rebbapragada et al. [44] conducted a well-defined cohort study among 55 HIV-infected and 36 uninfected Kenyan female commercial sex workers (CSWs). HSV-2 shedding is much more common in HIV-infected than HIV-uninfected women, perhaps due to HIV-induced depletion of mucosal immature dendritic cells exerting local HSV-2 immune control. In other clinical trials among HIV-1, HSV-2 co-infected persons, it was reported that HSV-2 suppression with acyclovir reduced the risk of HIV-1 disease progression [45], [46]. However, in one study of heterosexual HIV-1-serodiscordant couples among the partners who were infected with both HIV-1 and HSV-2, treatment with acyclovir for the suppression of HSV-2 infection did not decrease the transmission rate of HIV-1 to the uninfected partners, although acyclovir treatment reduced significantly plasma HIV-1 RNA levels and the incidence of genital ulcer disease [47].

Human cytomegalovirus (CMV), HSV-2, Neisseria gonorrhoeae, and other STIs can act as an important cofactor enhancing HIV secondary transmission either by breaching the epithelial barrier, recruiting HIV target cells to the genital tract, or by generating a pro-inflammatory local immune milieu [48], [49]. It was suggested that decreasing CMV transmission prenatally and postnatally might decrease the risk of HIV transmission among HIV-exposed-uninfected infants [50]. Sheth et al. [49] enrolled 26 chronically HIV-infected men who have sex with men (MSMs) and 15 HIV-uninfected men (six MSMs; nine heterosexuals). CMV shedding was associated with a 10-fold increase in HIV levels in semen, independent of HIV blood viral load CD4+ T cell count, and there was a strong linear correlation between the semen levels of HIV RNA and CMV DNA. In the US RCT trial, a total of 16 HIV-positive men and 10 HIV-negative men with HHV-8 were randomized to receive 8 weeks of valganciclovir or 8 weeks of placebo administered orally. Valganciclovir reduced oropharyngeal shedding of HHV-8 and CMV [51]. Several randomized controlled trials showed that male circumcision significantly reduced the risk of HIV acquisition in men in Africa [52]. Lack of male circumcision [53], [54], [55] can be considered as a facilitating factor or high levels of male circumcision and condom use can be considered as protective factors (please refer to the chapter on male circumcision). Facilitating factors are virtually all positively correlated with high-risk sex behaviors and are essential for epidemic HIV transmission, but they are difficult to quantify. Anal intercourse poses a higher risk of HIV transmission compared with vaginal intercourse because of the greater amount of tissue trauma that may occur [56], [57].

6 Screening for STIs

STIs facilitate both transmission and acquisition of HIV with relative risks of 2 to 5 [16]. Presence of any symptoms or signs suggestive of STIs should prompt immediate diagnostic evaluation and appropriate treatment. Because STIs are frequently asymptomatic, routine laboratory screening for STIs should be undertaken in high-risk populations where resources are available [58].

7 HIV counseling and testing

Since the first diagnostic HIV test in 1985, HIV testing has become easier, more sensitive, more accessible and less invasive. Unfortunately, national data indicate that a large percentage of new human immunodeficiency virus (HIV) diagnoses are made in the late stages of disease. In the United States, 40% of patients with newly diagnosed HIV infection develop AIDS within one year of testing. Furthermore, it has been estimated that one-fourth of the people living with HIV infection in the United States do not know they are infected and, thus, miss the opportunity to receive life-saving antiretroviral therapy [26], [27], [59]. That lack of awareness of HIV infection is critical from the public-health perspective as it is estimated that over 50% of new sexually transmitted HIV infections are due to people unaware of their HIV infection; and evidence strongly suggests that once individuals are made aware of their infection, they reduce their risk behavior and decrease the probability of transmitting infection [60]. In addition, people with acute HIV infection (which is defined as the first three weeks of infection) or early infection (the first six months) represent the greatest risk for transmission [3]. Therefore, HIV testing provides an opportunity for decreasing the continued incidence of HIV infection and for providing life-saving therapy to newly diagnosed patients. To decrease the number of people unaware of their HIV infection, in 2006, the Center for Disease Control and Prevention (CDC) expanded its HIV-testing recommendations [61]. The new CDC recommendations advocate voluntary “opt-out” HIV screening in healthcare settings for all adults instead of just screening traditionally “high-risk” patients. The recommendations also suggest eliminating requirements for written consent for HIV testing, annual re-testing for persons with known risk factors, and third-trimester screening for women who test negative for HIV early in pregnancy.

To date, the enzyme immunoassay (EIA) format is still the primary HIV antibody screening test in most settings. Assays are available to assess HIV-1 and HIV-2 separately or in combination [62]. The recent introduction of alternative fluids as suitable samples has allowed testing to go beyond the clinic setting. Oral fluid (mucosal transudate) testing is a valuable tool for outreach projects [63]. These noninvasive sample collections such as oral fluid and urine tend to decrease the chance of occupational exposure among health care workers.

8 Highly active anti-retroviral therapy (HAART)

The effects of anti-retroviral therapy have been assessed by using the surrogate markers such as plasma HIV viral load and CD4 cell count [64], [65]. Anti-retroviral combination therapy with two nucleoside analogues was shown to be superior to treatment with zidovudine monotherapy for slowing the progression of HIV disease [66]. In addition, it was reported that profound suppression of HIV replication could be obtained by the triple combination anti-retroviral therapy [67], [68]. The use of three or more anti-retroviral drugs is known as highly active anti-retroviral therapy (HAART). If only one drug was taken, HIV could quickly become resistant to it and the drug would stop working. Taking two or more anti-retrovirals at the same time vastly reduces the rate at which resistance might develop, making treatment more effective in the long-term [69]. There are more than 25 anti-retroviral drugs in 6 mechanistic classes, which are approved by Food and Drug Administration (FDA) for treatment of HIV infection (Table 2). Six classes of anti-retroviral agents are grouped by how these agents inhibit HIV replication and include the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor (FI), a CCR5 antagonist, and integrase strand transfer inhibitors (INSTIs). The initial HAART regimens usually consist of two NRTIs, plus a drug from one of three ARV classes: an INSTI, an NNRTI, or a PI. Several clinical trials and studies have showed HIV RNA decreases and CD4 T lymphocyte cell increases in HIV-infected patients who received HAART [70], [71], [72], [73]. Advances in antiretroviral therapy have made a change in HIV from an almost uniformly fatal disease to one that is a manageable chronic illness requiring continued evaluation and therapy.

Table 2: FDA-approved antiretroviral drugs for treating HIV/AIDS [74]

Anti-retroviral drug class	Abbreviation	Generic name	Mechanism of ction
Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs, nucleoside analogues)	3TC	lamivudine	NRTI interfere with the action of an HIV protein called reverse transcriptase, which the virus needs to make new copies of itself.
	ABC	abacavir
	AZT or ZDV	zidovudine
	d4T	stavudine
	ddC?	zalcitabine?
	ddI	didanosine
	FTC	emtricitabine
	TDF	tenofovir
Non-nucleoside reverse transcriptase inhibitors (NNRTIs, non-nucleosides)	DLV	delavirdine	NNRTIs also stop HIV from replicating within cells by inhibiting the reverse transcriptase protein.
	EFV	efavirenz
	ETR	etravirine
	NVP	nevirapine
	RPV	rilpivirine
Protease inhibitors (PIs)	APV	amprenavir?	PIs inhibit protease, which is another protein involved in the HIV replication process.
	FOS-APV	fosamprenavir
	ATV	atazanavir
	DRV	darunavir
	IDV	indinavir
	LPV/RTV	lopinavir/ritonavir
	NFV	nelfinavir
	RTV	ritonavir
	SQV	saquinavir
	TPV	tipranavir
Integrase strand transfer inhibitors (INSTIs)	RAL	raltegravir	Integrase inhibitors interfere with the integrase enzyme, which HIV needs to insert its genetic material into human cells.
	DTG	dolutegravir
	EVG	elvitegravir
Entry inhibitors	MVC	maraviroc	Entry inhibitors prevent HIV from binding to or entering human immune cells.
Fusion inhibitor	T-20	enfuvirtide	Fusion inhibitors prevent the binding, fusion, and entry of HIV to human cells

9 Urological manifestations of HIV infection

HIV infection in either early or late stages affects each of the major organs in the genitourinary system.

9.1 Urinary tract infections

The risk of bacterial and opportunistic infection, including urinary tract infections (UTIs), rises dramatically when the CD4 cell counts fall below 500/mm³ [75], [76]. The most common bacterial pathogens in HIV-infected patients are Escherichia coli, Enterobacter, Pseudomonas aeruginosa, Proteus spp., Klebsiella, Acinetobacter, Staphylococcus aureus, Group D Streptococcus, Serratia, and Salmonella spp. [76], [77], [78], [79], [80]. Atypical pathogens including fungi (Candida albicans, Aspergillus, Blastomyces, Cryptococcus neoformans, Cryptosporidia, Histoplasma capsulatum), parasites (Toxoplasma gondii, Pneumocystis carinii), mycobacteria (Mycobacterium tuberculosis, Mycobacterium avium complex), and viruses (cytomegalovirus and adenovirus) are often widely disseminated in patients with very low CD4 cell counts (usually <100/mm³) [79], [80], [81], [82], [83]. They may potentially affect any portion of the genitourinary tract, including the adrenals, kidneys, bladder, prostate, testes and epididymedes. When urinary cultures from 98 HIV-infected men were collected prospectively at six-monthly intervals over two years, and when they had signs and symptoms of UTI, one or more positive urinary cultures were found in 30% whose CD4 cell count was <200/mm³ and in 11% with a CD4 cell count of 200–500/mm³. No bacteriuria or symptomatic infective episodes were found in those with CD4 cell counts of >500/mm³ [75]. In autopsy studies of patients with AIDS, renal tuberculosis was identified in 6–23%. Although most of these patients had symptoms and signs of pulmonary tuberculosis, 20% had subclinical disease. The clinical diagnosis is made with urine tuberculosis culture, excretory urography, cystoscopy and biopsy with staining for acid-fast bacilli. Treatment requires at least three and sometimes four agents, including rifampicin, isoniazid, pyrazinamide and ethambutol for six to nine months, depending on sensitivity results [76], [79]. The incidence of acute bacterial prostatitis is 1% to 2% in the general population, whereas it is 3% in asymptomatic, HIV-infected patients and 14% in patients who have AIDS [84]. The incidence of prostatic abscesses in AIDS has decreased significantly with the advent of HAART, because they occur only in patients with very low CD4 cell counts [77]. In autopsy studies of patients with AIDS and systemic opportunistic infections, the prevalence of concomitant testicular infection is 25–39%. The causative organisms include Salmonella, Cytomegalovirus (CMV), Mycobacterium avium intracellulare (MAI), Toxoplasma, Histoplasma and Candida albicans [80], [85].

9.2 Malignancies

Many malignancies occur in HIV-infected patients. Possible mechanisms proposed that support malignancy formation include decreased immune surveillance, a direct effect of viral proteins, cytokine dysregulation, other immunologic factors, or viral cofactors [86], [87]. Vascular and lymphoreticular malignancies have been associated most strongly with HIV infection, particularly Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL). The risk of KS and NHL are increased 1,000- and 100-fold, respectively, among HIV-infected patients compared with the general population [88]. KS, systemic intermediate/high-grade B-cell NHL, and invasive cervical cancer are considered to be AIDS-defining malignancies. Many non-AIDS-defining malignancies have, however, also been found in greater frequency among those with HIV, including germ cell testicular tumors, renal cell carcinoma, and prostate cancer [89]. HAART radically changed the clinical spectrum of HIV infection in industrialized countries. The incidence of AIDS-associated malignancies decreased significantly after the introduction of HAART [90]. Systemic NHL incidence decreased less than KS and later than the other AIDS-defining illnesses. Consequently, lymphoma has become the most common AIDS-associated malignancy among patients receiving HAART [91]. KS can present as a systemic disease that affects internal organs, including the kidneys and testes [92], [93]. A herpes virus, called KS herpes virus or human herpes virus type 8, transmitted by sexual contact or through blood may be related to the development of KS in the HIV-positive population [77], [81]. Genital lesions appear in approximately 20% of patients who have KS, with <3% having the initial lesions on the penis [94]. Renal involvement of NHL in patients who have AIDS is 6% to 12%, and presentation may be bilateral [77], [79]. Renal cell carcinoma carries an 8.5-fold greater risk for HIV-infected patients compared with non-infected patients [95]. Retrospective review of 3,000 patients enrolled in an HIV clinic found a 50 times greater rate of testicular malignancy in the general population [96]. Compared with HIV noninfected patients, there is a greater risk of tumor bilaterality and a greater risk of high-grade testicular lymphoma [97]. Recently, Vianna and colleagues [98] examined a cohort of 534 men aged 49 years and older who had risk factors for HIV. Among older men, prostate-specific antigen (PSA) levels increased with age but did not differ by HIV status. The study recommended that standard PSA evaluations can be made with HIV-positive patients without the need for adjustments. HIV infection is associated with human papillomavirus (HPV)-related anogenital malignancies. HPV types 16 and 18 are considered high risk in anogenital malignancy formation of carcinoma in situ and squamous cell carcinoma [99]. Bowen's disease (Carcinoma in situ) of the penis, considered a premalignant lesion, appears more common in the HIV-infected population [100].

9.3 HIV-associated nephropathy (HIVAN)

HIV-associated nephropathy (HIVAN) is the most well-known and aggressive kidney disease in HIV-infected patients. With the widespread use of HAART, its prevalence is declining in industrialized countries [101]. The prevalence of HIVAN is reported to be 3.5% in HIV-infected clinic patients and 6.9% in autopsy series of HIV-infected patients [102]. Scientific evidence suggests that HAART can prevent the development of HIVAN [103], [104], [105]. Therefore, all patients with HIVAN should receive HAART. In addition, standard therapy for chronic kidney diseases are recommended for persons with HIVAN, including control of blood pressure, the use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers for the purpose of delaying disease progression or the need for renal replacement therapy [104], [105], [106]. HIV infection and related antiviral therapies are associated with diverse renal pathology, glomerular diseases, tubular injuries owing to tenofovir therapy, metabolic syndrome, obesity, and diabetic nephropathies. Clinicians should perform periodic screening of renal function and the possibility of HIV-associated glomerular or tubular diseases [105], [106].

9.4 Voiding dysfunction

Of patients with AIDS, 30-40% have neurological involvement, and in 20% this is the initial manifestations. In HIV-infected patients who present with voiding disturbances, an underlying neurological cause is present in 60%, and 90% of those already have AIDS-associated infections or tumors [79]. Urinary retention is the most common voiding dysfunction (54%) seen by urologists, although detrusor hyperreflexia (27%) and outflow obstruction (18%) have been documented during urodynamic study of AIDS patients with voiding symptoms [107], [108]. Voiding complaints often reflect the degree of systemic impairment and poor prognosis, although such symptoms often improve substantially after effective antiretroviral therapy [79].

9.5 Other urological manifestations

Several complications related to HAART such as urolithiasis and sexual dysfunction have been reported. The strongest association is with protease inhibitors, especially indinavir and atazanavir, and more recently darunavir [109]. Therefore, physicians should try to reduce the incidence of antiretroviral-induced nephrolithiasis by performing close surveillance of patients on long-term antiretroviral therapy [110]. Several studies have reported that 10-28% of patients receiving indinavir may develop a new form of urinary stones, known as “indinavir urolithiasis” [109], [110], [111], [112]. Pure indinavir stones are radiolucent and cannot be detected with either conventional radiography or CT. However, mixed stones consisting indinavir and calcium oxalate or phosphate salts have occasionally been reported in HIV-positive patients [113]. This adverse effect may be managed by the discontinuation of indinavir administration, urine acidification, hydration, alpha-blockers to facilitate stone passage, as well as the possible early insertion of bilateral double-J ureteral stents [114]. HAART, especially protease inhibitor-based therapy, also plays a role in sexual dysfunction [115], [116].

In a cohort study [117], the incidence of erectile dysfunction and decreased libido in HIV-positive homosexual men is 26%. In that study, in patients who were taking HAART, the incidence of reduced libido was 48% and the rate of erectile dysfunction was 25%. Decreased libido may be a result of raised estradiol level, low testosterone level, fatigue, depression and hypogonadism. However, Lallemand et al. [118] oppose the occurrence of sexual dysfunction in HIV-positive men taking protease inhibitors in their cross-sectional study. In another study, it was said that there was no association between erectile dysfunction or hypogonadism with the use of anti-retroviral medications [119]. Phosphodiesterase type-5 (PDE-5) inhibitors used for the treatment of erectile dysfunction also may interact with protease inhibitors, which increase the blood concentrations of PDE-5 inhibitors. Starting PDE-5 inhibitors at a lower dose with a caution for side-effect may be more appropriate in patients taking protease inhibitors [120].

10 Further research

Community-based RCTs or other clinical trials should test a range of alternative STI control strategies in a variety of different clinical settings in the future. Improved trials – especially more detailed estimates that measure a range of factors that include health seeking behavior and quality of treatment, as well as HIV, STI and other biological endpoints – will help us to identify the best possible intervention strategies for preventing the spread of HIV infection.

11 Conclusions

The current world-wide expansion of the AIDS epidemic is primarily driven by the sexual transmission of HIV. Evidence from intervention studies indicates that in the presence of other STIs, individuals are more likely to acquire HIV if exposed to the virus through sexual contact. Therefore, early detection and treatment of curable STIs can play a vital role in comprehensive programs to prevent sexual transmission of HIV. However, there is limited evidence from randomized controlled trials that control of STIs reduce HIV incidence at a population level. HIV both primarily and secondarily affects virtually every part of the genitourinary system. The availability of HAART has resulted in prolonging time to development of AIDS and improving AIDS survival rates. Urologists who treat genitourinary manifestations of HIV infection face a significant challenge in trying to restore and maintain normal genitourinary function.

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References

[1] Lee LK, Dinneen MD, Ahmad S. The urologist and the patient infected with human immunodeficiency virus or with acquired immunodeficiency syndrome. BJU Int. 2001 Oct;88(6):500-10.
[2] Joint United Nations Programme on HIV/AIDS. Global Fact Sheet. 2015 [cited 09 Feb 2016]. Available from: http://www.unaids.org/en/resources/campaigns/HowAIDSchangedeverything/factsheet
[3] Galvin SR, Cohen MS. The role of sexually transmitted diseases in HIV transmission. Nat Rev Microbiol. 2004 Jan;2(1):33-42. DOI: 10.1038/nrmicro794
[4] Royce RA, Seña A, Cates W Jr, Cohen MS. Sexual transmission of HIV. N Engl J Med. 1997 Apr;336(15):1072-8. DOI: 10.1056/NEJM199704103361507
[5] Abrams P, Khoury S, Grant A. Evidence--based medicine overview of the main steps for developing and grading guideline recommendations. Prog Urol. 2007 May;17(3):681-4. DOI: 10.1016/S1166-7087(07)92383-0
[6] ICUD Standards. U.S. Department of Health and Human Services Public Health Service Agency for Health Care Policy and Research; 1992. p. 115-127.
[7] Chin J, Bennett A. Heterosexual HIV transmission dynamics: implications for prevention and control. Int J STD AIDS. 2007 Aug;18(8):509-13. DOI: 10.1258/095646207781439667
[8] Padian N, Marquis L, Francis DP, Anderson RE, Rutherford GW, O'Malley PM, Winkelstein W Jr. Male-to-female transmission of human immunodeficiency virus. JAMA. 1987 Aug;258(6):788-90. DOI: 10.1001/jama.1987.03400060064030
[9] Padian NS, Shiboski SC, Jewell NP. Female-to-male transmission of human immunodeficiency virus. JAMA. 1991 Sep;266(12):1664-7. DOI: 10.1001/jama.1991.03470120066034
[10] Wawer MJ, Gray RH, Sewankambo NK, Serwadda D, Li X, Laeyendecker O, Kiwanuka N, Kigozi G, Kiddugavu M, Lutalo T, Nalugoda F, Wabwire-Mangen F, Meehan MP, Quinn TC. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis. 2005 May;191(9):1403-9. DOI: 10.1086/429411
[11] Chakraborty H, Sen PK, Helms RW, Vernazza PL, Fiscus SA, Eron JJ, Patterson BK, Coombs RW, Krieger JN, Cohen MS. Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model. AIDS. 2001 Mar;15(5):621-7. DOI: 10.1097/00002030-200103300-00012
[12] Hart CE, Lennox JL, Pratt-Palmore M, Wright TC, Schinazi RF, Evans-Strickfaden T, Bush TJ, Schnell C, Conley LJ, Clancy KA, Ellerbrock TV. Correlation of human immunodeficiency virus type 1 RNA levels in blood and the female genital tract. J Infect Dis. 1999 Apr;179(4):871-82. DOI: 10.1086/314656
[13] Chakraborty H, Helms RW, Sen PK, Cohen MS. Estimating correlation by using a general linear mixed model: evaluation of the relationship between the concentration of HIV-1 RNA in blood and semen. Stat Med. 2003 May;22(9):1457-64. DOI: 10.1002/sim.1505
[14] Gupta P, Mellors J, Kingsley L, Riddler S, Singh MK, Schreiber S, Cronin M, Rinaldo CR. High viral load in semen of human immunodeficiency virus type 1-infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. J Virol. 1997 Aug;71(8):6271-5.
[15] Cu-Uvin S, DeLong AK, Venkatesh KK, Hogan JW, Ingersoll J, Kurpewski J, De Pasquale MP, D'Aquila R, Caliendo AM. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS. 2010 Oct;24(16):2489-97. DOI: 10.1097/QAD.0b013e32833e5043
[16] Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect. 1999 Feb;75(1):3-17. DOI: 10.1136/sti.75.1.3
[17] Røttingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis. 2001 Oct;28(10):579-97. DOI: 10.1097/00007435-200110000-00005
[18] Coombs RW, Reichelderfer PS, Landay AL. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS. 2003 Mar;17(4):455-80. DOI: 10.1097/01.aids.0000042970.95433.f9
[19] Dyer JR, Gilliam BL, Eron JJ Jr, Grosso L, Cohen MS, Fiscus SA. Quantitation of human immunodeficiency virus type 1 RNA in cell free seminal plasma: comparison of NASBA with Amplicor reverse transcription-PCR amplification and correlation with quantitative culture. J Virol Methods. 1996 Jul;60(2):161-70. DOI: 10.1016/0166-0934(96)02063-0
[20] Vernazza PL, Gilliam BL, Dyer J, Fiscus SA, Eron JJ, Frank AC, Cohen MS. Quantification of HIV in semen: correlation with antiviral treatment and immune status. AIDS. 1997 Jul;11(8):987-93. DOI: 10.1097/00002030-199708000-00006
[21] Uvin SC, Caliendo AM. Cervicovaginal human immunodeficiency virus secretion and plasma viral load in human immunodeficiency virus-seropositive women. Obstet Gynecol. 1997 Nov;90(5):739-43. DOI: 10.1016/S0029-7844(97)00411-0
[22] Coombs RW, Speck CE, Hughes JP, Lee W, Sampoleo R, Ross SO, Dragavon J, Peterson G, Hooton TM, Collier AC, Corey L, Koutsky L, Krieger JN. Association between culturable human immunodeficiency virus type 1 (HIV-1) in semen and HIV-1 RNA levels in semen and blood: evidence for compartmentalization of HIV-1 between semen and blood. J Infect Dis. 1998 Feb;177(2):320-30. DOI: 10.1086/514213
[23] Dyer JR, Gilliam BL, Eron JJ Jr, Cohen MS, Fiscus SA, Vernazza PL. Shedding of HIV-1 in semen during primary infection. AIDS. 1997 Mar;11(4):543-5.
[24] Stebbing J, Moyle G. The clades of HIV: their origins and clinical significance. AIDS Rev. 2003 Oct-Dec;5(4):205-13.
[25] Buonaguro L, Tornesello ML, Buonaguro FM. Human immunodeficiency virus type 1 subtype distribution in the worldwide epidemic: pathogenetic and therapeutic implications. J Virol. 2007 Oct;81(19):10209-19. DOI: 10.1128/JVI.00872-07
[26] Kiwanuka N, Laeyendecker O, Robb M, Kigozi G, Arroyo M, McCutchan F, Eller LA, Eller M, Makumbi F, Birx D, Wabwire-Mangen F, Serwadda D, Sewankambo NK, Quinn TC, Wawer M, Gray R. Effect of human immunodeficiency virus Type 1 (HIV-1) subtype on disease progression in persons from Rakai, Uganda, with incident HIV-1 infection. J Infect Dis. 2008 Mar;197(5):707-13. DOI: 10.1086/527416
[27] Gao F, Robertson DL, Morrison SG, Hui H, Craig S, Decker J, Fultz PN, Girard M, Shaw GM, Hahn BH, Sharp PM. The heterosexual human immunodeficiency virus type 1 epidemic in Thailand is caused by an intersubtype (A/E) recombinant of African origin. J Virol. 1996 Oct;70(10):7013-29.
[28] van Harmelen J, Wood R, Lambrick M, Rybicki EP, Williamson AL, Williamson C. An association between HIV-1 subtypes and mode of transmission in Cape Town, South Africa. AIDS. 1997 Jan;11(1):81-7. DOI: 10.1097/00002030-199701000-00012
[29] Avila MM, Pando MA, Carrion G, Peralta LM, Salomon H, Carrillo MG, Sanchez J, Maulen S, Hierholzer J, Marinello M, Negrete M, Russell KL, Carr JK. Two HIV-1 epidemics in Argentina: different genetic subtypes associated with different risk groups. J Acquir Immune Defic Syndr. 2002 Apr;29(4):422-6. DOI: 10.1097/00126334-200204010-00015
[30] Buonaguro L, Tagliamonte M, Tornesello M, Buonaguro FM. Evolution of the HIV-1 V3 region in the Italian epidemic. New Microbiol. 2007 Jan;30(1):1-11.
[31] Buonaguro L, Tagliamonte M, Tornesello ML, Buonaguro FM. Genetic and phylogenetic evolution of HIV-1 in a low subtype heterogeneity epidemic: the Italian example. Retrovirology. 2007 May;4:34. DOI: 10.1186/1742-4690-4-34
[32] Tagliamonte M, Vidal N, Tornesello ML, Peeters M, Buonaguro FM, Buonaguro L. Genetic and phylogenetic characterization of structural genes from non-B HIV-1 subtypes in Italy. AIDS Res Hum Retroviruses. 2006 Oct;22(10):1045-51. DOI: 10.1089/aid.2006.22.1045
[33] Grosskurth H, Mosha F, Todd J, Mwijarubi E, Klokke A, Senkoro K, Mayaud P, Changalucha J, Nicoll A, ka-Gina G, et al. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial. Lancet. 1995 Aug 26;346(8974):530-6. DOI: 10.1016/S0140-6736(95)91380-7
[34] Wawer MJ, Sewankambo NK, Serwadda D, Quinn TC, Paxton LA, Kiwanuka N, Wabwire-Mangen F, Li C, Lutalo T, Nalugoda F, Gaydos CA, Moulton LH, Meehan MO, Ahmed S, Gray RH. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Rakai Project Study Group. Lancet. 1999 Feb 13;353(9152):525-35. DOI: 10.1016/S0140-6736(98)06439-3
[35] Gray RH, Wabwire-Mangen F, Kigozi G, Sewankambo NK, Serwadda D, Moulton LH, Quinn TC, O'Brien KL, Meehan M, Abramowsky C, Robb M, Wawer MJ. Randomized trial of presumptive sexually transmitted disease therapy during pregnancy in Rakai, Uganda. Am J Obstet Gynecol. 2001 Nov;185(5):1209-17. DOI: 10.1067/mob.2001.118158
[36] Kamali A, Quigley M, Nakiyingi J, Kinsman J, Kengeya-Kayondo J, Gopal R, Ojwiya A, Hughes P, Carpenter LM, Whitworth J. Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial. Lancet. 2003 Feb 22;361(9358):645-52. DOI: 10.1016/S0140-6736(03)12598-6
[37] Hay P. HIV transmission and sexually transmitted infections. Clin Med (Lond). 2008 Jun;8(3):323-6. DOI: 10.7861/clinmedicine.8-3-323
[38] Gregson S, Adamson S, Papaya S, Mundondo J, Nyamukapa CA, Mason PR, Garnett GP, Chandiwana SK, Foster G, Anderson RM. Impact and process evaluation of integrated community and clinic-based HIV-1 control: a cluster-randomised trial in eastern Zimbabwe. PLoS Med. 2007 Mar;4(3):e102. DOI: 10.1371/journal.pmed.0040102
[39] Ng BE, Butler LM, Horvath T, Rutherford GW. Population-based biomedical sexually transmitted infection control interventions for reducing HIV infection. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001220. DOI: 10.1002/14651858.CD001220.pub3
[40] Gray RH, Wawer MJ. Reassessing the hypothesis on STI control for HIV prevention. Lancet. 2008 Jun 21;371(9630):2064-5. DOI: 10.1016/S0140-6736(08)60896-X
[41] O'Farrell N. Control of sexually transmitted infections for HIV prevention. Lancet. 2008 Oct 11;372(9646):1297; author reply 1297-8. DOI: 10.1016/S0140-6736(08)61540-8
[42] Nagot N, Ouédraogo A, Foulongne V, Konaté I, Weiss HA, Vergne L, Defer MC, Djagbaré D, Sanon A, Andonaba JB, Becquart P, Segondy M, Vallo R, Sawadogo A, Van de Perre P, Mayaud P; ANRS 1285 Study Group. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med. 2007 Feb;356(8):790-9. DOI: 10.1056/NEJMoa062607
[43] Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS. 2006 Jan;20(1):73-83. DOI: 10.1097/01.aids.0000198081.09337.a7
[44] Rebbapragada A, Wachihi C, Pettengell C, Sunderji S, Huibner S, Jaoko W, Ball B, Fowke K, Mazzulli T, Plummer FA, Kaul R. Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract. AIDS. 2007 Mar;21(5):589-98. DOI: 10.1097/QAD.0b013e328012b896
[45] Lingappa JR, Baeten JM, Wald A, Hughes JP, Thomas KK, Mujugira A, Mugo N, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de Bruyn G, Gray GE, McIntyre JA, Manongi R, Kapiga S, Coetzee D, Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany S, Rees H, Vwalika B, Magaret AS, Wang RS, Kidoguchi L, Barnes L, Ridzon R, Corey L, Celum C; Partners in Prevention HSV/HIV Transmission Study Team. Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial. Lancet. 2010 Mar 6;375(9717):824-33. DOI: 10.1016/S0140-6736(09)62038-9
[46] Reynolds SJ, Makumbi F, Newell K, Kiwanuka N, Ssebbowa P, Mondo G, Boaz I, Wawer MJ, Gray RH, Serwadda D, Quinn TC. Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial. Lancet Infect Dis. 2012 Jun;12(6):441-8. DOI: 10.1016/S1473-3099(12)70037-3
[47] Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS, Mugo N, Mujugira A, Baeten JM, Mullins JI, Hughes JP, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de Bruyn G, Gray GE, McIntyre JA, Manongi R, Kapiga S, Coetzee D, Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany S, Rees H, Vwalika B, Stevens W, Campbell MS, Thomas KK, Coombs RW, Morrow R, Whittington WL, McElrath MJ, Barnes L, Ridzon R, Corey L; Partners in Prevention HSV/HIV Transmission Study Team. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010 Feb;362(5):427-39. DOI: 10.1056/NEJMoa0904849
[48] Kaul R, Pettengell C, Sheth PM, Sunderji S, Biringer A, MacDonald K, Walmsley S, Rebbapragada A. The genital tract immune milieu: an important determinant of HIV susceptibility and secondary transmission. J Reprod Immunol. 2008 Jan;77(1):32-40. DOI: 10.1016/j.jri.2007.02.002
[49] Sheth PM, Danesh A, Sheung A, Rebbapragada A, Shahabi K, Kovacs C, Halpenny R, Tilley D, Mazzulli T, MacDonald K, Kelvin D, Kaul R. Disproportionately high semen shedding of HIV is associated with compartmentalized cytomegalovirus reactivation. J Infect Dis. 2006 Jan;193(1):45-8. DOI: 10.1086/498576
[50] Ellington SR, Clarke KE, Kourtis AP. Cytomegalovirus Infection in Human Immunodeficiency Virus (HIV)-Exposed and HIV-Infected Infants: A Systematic Review. J Infect Dis. 2016 Mar;213(6):891-900. DOI: 10.1093/infdis/jiv549
[51] Casper C, Krantz EM, Corey L, Kuntz SR, Wang J, Selke S, Hamilton S, Huang ML, Wald A. Valganciclovir for suppression of human herpesvirus-8 replication: a randomized, double-blind, placebo-controlled, crossover trial. J Infect Dis. 2008 Jul;198(1):23-30. DOI: 10.1086/588820
[52] Mills E, Cooper C, Anema A, Guyatt G. Male circumcision for the prevention of heterosexually acquired HIV infection: a meta-analysis of randomized trials involving 11,050 men. HIV Med. 2008 Jul;9(6):332-5. DOI: 10.1111/j.1468-1293.2008.00596.x
[53] Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med. 2005 Nov;2(11):e298. DOI: 10.1371/journal.pmed.0020298
[54] Bailey RC, Moses S, Parker CB, Agot K, Maclean I, Krieger JN, Williams CF, Campbell RT, Ndinya-Achola JO. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007 Feb 24;369(9562):643-56. DOI: 10.1016/S0140-6736(07)60312-2
[55] Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, Kiwanuka N, Moulton LH, Chaudhary MA, Chen MZ, Sewankambo NK, Wabwire-Mangen F, Bacon MC, Williams CF, Opendi P, Reynolds SJ, Laeyendecker O, Quinn TC, Wawer MJ. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007 Feb 24;369(9562):657-66. DOI: 10.1016/S0140-6736(07)60313-4
[56] Powers KA, Poole C, Pettifor AE, Cohen MS. Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet Infect Dis. 2008 Sep;8(9):553-63. DOI: 10.1016/S1473-3099(08)70156-7
[57] Katz IT, Wright AA. Circumcision--a surgical strategy for HIV prevention in Africa. N Engl J Med. 2008 Dec;359(23):2412-5. DOI: 10.1056/NEJMp0805791
[58] Marrazzo J. Syphilis and other sexually transmitted diseases in HIV infection. Top HIV Med. 2007 Feb-Mar;15(1):11-6.
[59] Centers for Disease Control and Prevention (CDC). Twenty-five years of HIV/AIDS--United States, 1981-2006. MMWR Morb Mortal Wkly Rep. 2006 Jun;55(21):585-9.
[60] Marks G, Crepaz N, Senterfitt JW, Janssen RS. Meta-analysis of high-risk sexual behavior in persons aware and unaware they are infected with HIV in the United States: implications for HIV prevention programs. J Acquir Immune Defic Syndr. 2005 Aug;39(4):446-53. DOI: 10.1097/01.qai.0000151079.33935.79
[61] Branson BM, Handsfield HH, Lampe MA, Janssen RS, Taylor AW, Lyss SB, Clark JE; Centers for Disease Control and Prevention (CDC). Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006 Sep 22;55(RR-14):1-17; quiz CE1-4.
[62] Branson BM. State of the art for diagnosis of HIV infection. Clin Infect Dis. 2007 Dec;45 Suppl 4:S221-5. DOI: 10.1086/522541
[63] Wesolowski LG, MacKellar DA, Facente SN, Dowling T, Ethridge SF, Zhu JH, Sullivan PS; Post-marketing Surveillance Team. Post-marketing surveillance of OraQuick whole blood and oral fluid rapid HIV testing. AIDS. 2006 Aug;20(12):1661-6. DOI: 10.1097/01.aids.0000238413.13442.ed
[64] Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Sáag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. International AIDS Society-USA. JAMA. 1996 Jul;276(2):146-54. DOI: 10.1001/jama.1996.03540020068031
[65] Katzenstein DA, Hammer SM, Hughes MD, Gundacker H, Jackson JB, Fiscus S, Rasheed S, Elbeik T, Reichman R, Japour A, Merigan TC, Hirsch MS. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med. 1996 Oct;335(15):1091-8. DOI: 10.1056/NEJM199610103351502
[66] Hammer SM, Katzenstein DA, Hughes MD, Gundacker H, Schooley RT, Haubrich RH, Henry WK, Lederman MM, Phair JP, Niu M, Hirsch MS, Merigan TC. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. N Engl J Med. 1996 Oct;335(15):1081-90. DOI: 10.1056/NEJM199610103351501
[67] Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 Sep;337(11):725-33. DOI: 10.1056/NEJM199709113371101
[68] Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD, Valentine FT, Jonas L, Meibohm A, Emini EA, Chodakewitz JA. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997 Sep;337(11):734-9. DOI: 10.1056/NEJM199709113371102
[69] Yeni P. Update on HAART in HIV. J Hepatol. 2006;44(1 Suppl):S100-3. DOI: 10.1016/j.jhep.2005.11.021
[70] Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2016 [cited 5 March 2016]. Available from: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
[71] Moore RD, Bartlett JG. Dramatic decline in the HIV-1 RNA level over calendar time in a large urban HIV practice. Clin Infect Dis. 2011 Sep;53(6):600-4. DOI: 10.1093/cid/cir467
[72] Lee FJ, Amin J, Carr A. Efficacy of initial antiretroviral therapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks' follow-up. PLoS ONE. 2014;9(5):e97482. DOI: 10.1371/journal.pone.0097482
[73] Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, Eron JJ, Günthard HF, Hammer SM, Reiss P, Richman DD, Rizzardini G, Thomas DL, Jacobsen DM, Volberding PA. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012 Jul;308(4):387-402. DOI: 10.1001/jama.2012.7961
[74] U.S. Food and Drug Administration. Drugs used in the treatment of HIV infection. [cited 2016 Mar 13]. Available from: http://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-hiv-medicines.
[75] Hoepelman AI, van Buren M, van den Broek J, Borleffs JC. Bacteriuria in men infected with HIV-1 is related to their immune status (CD4+ cell count). AIDS. 1992 Feb;6(2):179-84. DOI: 10.1097/00002030-199202000-00006
[76] Lee LK, Dinneen MD, Ahmad S. The urologist and the patient infected with human immunodeficiency virus or with acquired immunodeficiency syndrome. BJU Int. 2001 Oct;88(6):500-10. DOI: 10.1046/j.1464-410X.2001.02376.x
[77] Hyun G, Lowe FC. AIDS and the urologist. Urol Clin North Am. 2003 Feb;30(1):101-9. DOI: 10.1016/S0094-0143(02)00124-6
[78] Miles BJ, Melser M, Farah R, Markowitz N, Fisher E. The urological manifestations of the acquired immunodeficiency syndrome. J Urol. 1989;142(3):771-3. DOI: 10.1016/S0022-5347(17)38883-3
[79] Heyns CF, Fisher M. The urological management of the patient with acquired immunodeficiency syndrome. BJU Int. 2005 Apr;95(5):709-16. DOI: 10.1111/j.1464-410X.2004.05435.x
[80] Shindel AW, Akhavan A, Sharlip ID. Urologic aspects of HIV infection. Med Clin North Am. 2011 Jan;95(1):129-51. DOI: 10.1016/j.mcna.2010.08.017
[81] Steels BW, Carson CC. Recognizing the urologic manifestations of HIV and AIDS. Contemp Urol. 1997;9:39-53.
[82] Lebovitch S, Mydlo JH. HIV-AIDS: urologic considerations. Urol Clin North Am. 2008 Feb;35(1):59-68; vi. DOI: 10.1016/j.ucl.2007.09.001
[83] O'Regan S, Russo P, Lapointe N, Rousseau E. AIDS and the urinary tract. J Acquir Immune Defic Syndr. 1990;3(3):244-51.
[84] Leport C, Rousseau F, Perronne C, Salmon D, Joerg A, Vilde JL. Bacterial prostatitis in patients infected with the human immunodeficiency virus. J Urol. 1989 Feb;141(2):334-6. DOI: 10.1016/S0022-5347(17)40759-2
[85] De Paepe ME, Waxman M. Testicular atrophy in AIDS: a study of 57 autopsy cases. Hum Pathol. 1989 Mar;20(3):210-4. DOI: 10.1016/0046-8177(89)90125-1
[86] Blattner WA. Human retroviruses: their role in cancer. Proc Assoc Am Physicians. 1999 Nov-Dec;111(6):563-72. DOI: 10.1046/j.1525-1381.1999.99210.x
[87] Bellan C, De Falco G, Lazzi S, Leoncini L. Pathologic aspects of AIDS malignancies. Oncogene. 2003 Sep;22(42):6639-45. DOI: 10.1038/sj.onc.1206815
[88] Dal Maso L, Serraino D, Franceschi S. Epidemiology of AIDS-related tumours in developed and developing countries. Eur J Cancer. 2001 Jul;37(10):1188-201. DOI: 10.1016/S0959-8049(01)00120-4
[89] Silverberg MJ, Abrams DI. AIDS-defining and non-AIDS-defining malignancies: cancer occurrence in the antiretroviral therapy era. Curr Opin Oncol. 2007 Sep;19(5):446-51. DOI: 10.1097/CCO.0b013e3282c8c90d
[90] Bower M, Palmieri C, Dhillon T. AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis. 2006 Feb;19(1):14-9.
[91] Grulich AE, Li Y, McDonald AM, Correll PK, Law MG, Kaldor JM. Decreasing rates of Kaposi's sarcoma and non-Hodgkin's lymphoma in the era of potent combination anti-retroviral therapy. AIDS. 2001 Mar;15(5):629-33.
[92] Pollok RC, Francis N, Cliff S, Nelson N, Gazzard B. Kaposi's sarcoma in the kidney. Int J STD AIDS. 1995 Jul-Aug;6(4):289-90. DOI: 10.1177/095646249500600414
[93] Weil DA, Ruckle HC, Lui PD, Saukel W. Kaposi's sarcoma of the testicle. AIDS Read. 1999 Oct;9(7):455-6, 461.
[94] Lowe FC, Lattimer DG, Metroka CE. Kaposi's sarcoma of the penis in patients with acquired immunodeficiency syndrome. J Urol. 1989 Dec;142(6):1475-7. DOI: 10.1016/S0022-5347(17)39129-2
[95] Baynham SA, Katner HP, Cleveland KB. Increased prevalence of renal cell carcinoma in patients with HIV infection. AIDS Patient Care STDS. 1997 Jun;11(3):161-5. DOI: 10.1089/apc.1997.11.161
[96] Wilson WT, Frenkel E, Vuitch F, Sagalowsky AI. Testicular tumors in men with human immunodeficiency virus. J Urol. 1992 Apr;147(4):1038-40. DOI: 10.1016/S0022-5347(17)37458-X
[97] Armenakas NA, Schevchuk MM, Brodherson M, Fracchia JA. AIDS presenting as primary testicular lymphoma. Urology. 1992 Aug;40(2):162-4. DOI: 10.1016/0090-4295(92)90519-3
[98] Vianna LE, Lo Y, Klein RS. Serum prostate-specific antigen levels in older men with or at risk of HIV infection. HIV Med. 2006 Oct;7(7):471-6. DOI: 10.1111/j.1468-1293.2006.00410.x
[99] zur Hausen H, de Villiers EM. Human papillomaviruses. Annu Rev Microbiol. 1994;48:427-47. DOI: 10.1146/annurev.mi.48.100194.002235
[100] Wang CY, Brodland DG, Su WP. Skin cancers associated with acquired immunodeficiency syndrome. Mayo Clin Proc. 1995 Aug;70(8):766-72.
[101] Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol. 2005 Aug;16(8):2412-20. DOI: 10.1681/ASN.2005040340
[102] Shahinian V, Rajaraman S, Borucki M, Grady J, Hollander WM, Ahuja TS. Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis. 2000 May;35(5):884-8. DOI: 10.1016/S0272-6386(00)70259-9
[103] Winston JA, Bruggeman LA, Ross MD, Jacobson J, Ross L, D'Agati VD, Klotman PE, Klotman ME. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med. 2001 Jun;344(26):1979-84. DOI: 10.1056/NEJM200106283442604
[104] Atta MG, Gallant JE, Rahman MH, Nagajothi N, Racusen LC, Scheel PJ, Fine DM. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant. 2006 Oct;21(10):2809-13. DOI: 10.1093/ndt/gfl337
[105] Rosenberg AZ, Naicker S, Winkler CA, Kopp JB. HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment. Nat Rev Nephrol. 2015 Mar;11(3):150-60. DOI: 10.1038/nrneph.2015.9
[106] Atta MG, Lucas GM, Fine DM. HIV-associated nephropathy: epidemiology, pathogenesis, diagnosis and management. Expert Rev Anti Infect Ther. 2008 Jun;6(3):365-71. DOI: 10.1586/14787210.6.3.365
[107] Kane CJ, Bolton DM, Connolly JA, Tanagho EA. Voiding dysfunction in human immunodeficiency virus infections. J Urol. 1996 Feb;155(2):523-6. DOI: 10.1097/00005392-199602000-00031
[108] Hermieu JF, Delmas V, Boccon-Gibod L. Micturition disturbances and human immunodeficiency virus infection. J Urol. 1996 Jul;156(1):157-9. DOI: 10.1016/S0022-5347(01)65972-X
[109] Bruce RG, Munch LC, Hoven AD, Jerauld RS, Greenburg R, Porter WH, Rutter PW. Urolithiasis associated with the protease inhibitor indinavir. Urology. 1997;50(4):513–8. DOI: 10.1016/S0090-4295(97)00399-3
[110] Izzedine H, Lescure FX, Bonnet F. HIV medication-based urolithiasis. Clin Kidney J. 2014;7(2):121-6.
[111] Gentle DL, Stoller ML, Jarrett TW, Ward JF, Geib KS, Wood AF. Protease inhibitor-induced urolithiasis. Urology. 1997 Oct;50(4):508-11. DOI: 10.1016/S0090-4295(97)00401-9
[112] Salahuddin S, Hsu YS, Buchholz NP, Dieleman JP, Gyssens IC, Kok DJ. Is indinavir crystalluria an indicator for indinavir stone formation? AIDS. 2001 May;15(8):1079-80. DOI: 10.1097/00002030-200105250-00026
[113] Daudon M, Estepa L, Viard JP, Joly D, Jungers P. Urinary stones in HIV-1-positive patients treated with indinavir. Lancet. 1997;349(9061):1294–5. DOI: 10.1016/S0140-6736(05)62506-8
[114] Kalaitzis C, Passadakis P, Giannakopoulos S, Panagoutsos S, Mpantis E, Triantafyllidis A, Touloupidis S, Vargemezis V. Urological management of indinavir-associated acute renal failure in HIV-positive patients. Int Urol Nephrol. 2007;39(3):743-6. DOI: 10.1007/s11255-006-9154-x
[115] Schrooten W, Colebunders R, Youle M, Molenberghs G, Dedes N, Koitz G, Finazzi R, de Mey I, Florence E, Dreezen C; Eurosupport Study Group. Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment. AIDS. 2001 May;15(8):1019-23. DOI: 10.1097/00002030-200105250-00010
[116] Sollima S, Osio M, Muscia F, Gambaro P, Alciati A, Zucconi M, Maga T, Adorni F, Bini T, d'Arminio Monforte A. Protease inhibitors and erectile dysfunction. AIDS. 2001 Nov;15(17):2331-3. DOI: 10.1097/00002030-200111230-00020
[117] Lamba H, Goldmeier D, Mackie NE, Scullard G. Antiretroviral therapy is associated with sexual dysfunction and with increased serum oestradiol levels in men. Int J STD AIDS. 2004 Apr;15(4):234-7. DOI: 10.1258/095646204773557749
[118] Lallemand F, Salhi Y, Linard F, Giami A, Rozenbaum W. Sexual dysfunction in 156 ambulatory HIV-infected men receiving highly active antiretroviral therapy combinations with and without protease inhibitors. J Acquir Immune Defic Syndr. 2002 Jun;30(2):187-90.
[119] Crum-Cianflone NF, Bavaro M, Hale B, Amling C, Truett A, Brandt C, Pope B, Furtek K, Medina S, Wallace MR. Erectile dysfunction and hypogonadism among men with HIV. AIDS Patient Care STDS. 2007 Jan;21(1):9-19. DOI: 10.1089/apc.2006.0071
[120] Merry C, Barry MG, Ryan M, Tjia JF, Hennessy M, Eagling VA, Mulcahy F, Back DJ. Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. AIDS. 1999 Oct;13(15):F101-7. DOI: 10.1097/00002030-199910220-00001
[121] Sangani P, Rutherford G, Wilkinson D. Population-based interventions for reducing sexually transmitted infections, including HIV infection. Cochrane Database Syst Rev. 2004;(2):CD001220. DOI: 10.1002/14651858.CD001220.pub2
[122] Ng BE, Butler LM, Horvath T, Rutherford GW. Population-based biomedical sexually transmitted infection control interventions for reducing HIV infection. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001220. DOI: 10.1002/14651858.CD001220.pub3
[123] Atashili J, Poole C, Ndumbe PM, Adimora AA, Smith JS. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS. 2008 Jul;22(12):1493-501. DOI: 10.1097/QAD.0b013e3283021a37
[124] Cameron DW, Simonsen JN, D'Costa LJ, Ronald AR, Maitha GM, Gakinya MN, Cheang M, Ndinya-Achola JO, Piot P, Brunham RC, et al. Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men. Lancet. 1989 Aug 19;2(8660):403-7. DOI: 10.1016/S0140-6736(89)90589-8
[125] Plummer FA, Simonsen JN, Cameron DW, Ndinya-Achola JO, Kreiss JK, Gakinya MN, Waiyaki P, Cheang M, Piot P, Ronald AR. Cofactors in male-female sexual transmission of human immunodeficiency virus type 1. J Infect Dis. 1991 Feb;163(2):233-9. DOI: 10.1093/infdis/163.2.233
[126] Laga M, Manoka A, Kivuvu M, Malele B, Tuliza M, Nzila N, Goeman J, Behets F, Batter V, Alary M. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS. 1993 Jan;7(1):95-102. DOI: 10.1097/00002030-199301000-00015
[127] Taha TE, Hoover DR, Dallabetta GA, Kumwenda NI, Mtimavalye LA, Yang LP, Liomba GN, Broadhead RL, Chiphangwi JD, Miotti PG. Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV. AIDS. 1998 Sep;12(13):1699-706. DOI: 10.1097/00002030-199813000-00019
[128] Martin HL, Richardson BA, Nyange PM, Lavreys L, Hillier SL, Chohan B, Mandaliya K, Ndinya-Achola JO, Bwayo J, Kreiss J. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis. 1999 Dec;180(6):1863-8. DOI: 10.1086/315127
[129] Myer L, Denny L, Telerant R, Souza Md, Wright TC Jr, Kuhn L. Bacterial vaginosis and susceptibility to HIV infection in South African women: a nested case-control study. J Infect Dis. 2005 Oct;192(8):1372-80. DOI: 10.1086/462427
[130] Cohen MS, Hoffman IF, Royce RA, Kazembe P, Dyer JR, Daly CC, Zimba D, Vernazza PL, Maida M, Fiscus SA, Eron JJ Jr. Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1. AIDSCAP Malawi Research Group. Lancet. 1997 Jun 28;349(9069):1868-73. DOI: 10.1016/S0140-6736(97)02190-9
[131] Ghys PD, Fransen K, Diallo MO, Ettiègne-Traoré V, Coulibaly IM, Yeboué KM, Kalish ML, Maurice C, Whitaker JP, Greenberg AE, Laga M. The associations between cervicovaginal HIV shedding, sexually transmitted diseases and immunosuppression in female sex workers in Abidjan, Côte d'Ivoire. AIDS. 1997 Oct;11(12):F85-93. DOI: 10.1097/00002030-199712000-00001
[132] Stamm WE, Handsfield HH, Rompalo AM, Ashley RL, Roberts PL, Corey L. The association between genital ulcer disease and acquisition of HIV infection in homosexual men. JAMA. 1988 Sep;260(10):1429-33. DOI: 10.1001/jama.1988.03410100119036