Variable Rates of Sexual Transmission

Multiple cofactors affect HIV transmission, which is why estimates vary on the relative risk for specific exposures (see Table 14–2) (Royce et al, 1997; Vernazza and Eron, 1997). The probability of HIV transmission associated with unprotected vaginal sexual intercourse is not constant from one contact to another: estimates range from 0.0005 to 0.002 per episode, in the absence of cofactors (Carael et al, 2004).

A recent meta-analysis of observational studies provided risk estimates for per sexual act transmission of HIV-1 among heterosexuals (Boily et al, 2009). The study included 43 publications, based on work in 25 different study populations. The pooled risk estimates suggest that female-to-male (0.04% per act [95% confidence interval [CI] 0.01-0.14]) and male-to-female (0.08% per act [95% CI 0.06-0.11]) HIV transmission rates are low in high-income countries. In contrast, much higher HIV transmission rates occur in low-income countries with female-to-male (0.38% per act [95% CI 0.13-1.10]) and male-to-female (0.30% per act [95% CI 0.14-0.63]) HIV transmission rates, even in the absence of commercial sex exposure. In multivariate analyses, transmission rates were influenced by gender, setting (high- vs. low-income countries), and antenatal HIV prevalence. As expected, the pooled risk estimate was higher for receptive anal intercourse (1.7% per act [95% CI 0.3-8.9]) and for the presence or history of genital ulcers in either couple member (5.3% per act [95% CI 1.4-19.5]).

Sexually Transmitted Infections

The presence of STIs suggests a marked risk of concurrent HIV. First, the modes of transmission of HIV and other STIs are similar. Second, genital ulcers as well as nonulcerative STIs facilitate HIV transmission (Cameron et al, 1989). Ulcerative STIs, including herpes, syphilis, and chancroid, enhance susceptibility to HIV per sexual act. Nonulcerative STIs, including gonorrhea, chlamydial infections, and trichomoniasis, are independent risk factors for HIV, with relative risks of 2.7 to 3.5 (Laga et al, 1994). Because syphilis facilitates acquisition and transmission of HIV, recent outbreaks of syphilis among men who have sex with men in major U.S. cities and reported increases in sexual behavior have raised concerns about potential increases in HIV transmission (Centers for Disease Control and Prevention, 2004).

Several studies report conflicting results for aggressive diagnosis and treatment of STIs to limit HIV infection in high-risk populations. One study from Uganda employed syndromic management of STIs in an area where the epidemic was in its early stages with less than 1% of the adult population being infected at study inception. HIV incidence decreased in communities where the intervention was undertaken compared with control communities (Grosskurth et al, 1995). Different findings were reported in a study from Tanzania that employed periodic mass STI treatment of at-risk adults. This study found no decrease in HIV incidence (Wawer et al, 1999). In the later study the epidemic was more advanced with more than 16% of the adult population being infected at study inception. In addition there was a high rate of concomitant genital herpes that was not treated. Taken together, these findings suggest that efforts to decrease HIV spread through treating STIs should focus on specific treatment for individual patients, with aggressive diagnosis and treatment of STIs that are common in the community. The potential benefit of STI control programs may also prove greatest in areas of lower HIV prevalence. In communities where the epidemic is widespread, the likelihood of encountering a new partner who is HIV infected may be substantial, so the benefit of modifying a cofactor may be more limited (Mayer and Safren, 2004).

Antiretroviral Therapy and Genital Secretions

Only a small proportion of sexual exposures result in HIV transmission (Anderson and May, 1988). Transmission may occur by exposure to cell-free or cell-associated virus, and different factors may affect expression of virus concentrations in different body fluids (i.e., blood, semen, or cervicovaginal secretions) (Krieger et al, 1998; Chakraborty et al, 2001; Mayer and Safren, 2004). Although lower blood HIV levels are associated with lower transmission rates (Quinn et al, 2000), antiretroviral therapy may not make HIV-infected people noninfectious. In fact, sexual transmission of multidrug-resistant HIV has been well documented (Boden et al, 1999; Little et al, 1999). These observations underscore the need for HIV-infected patients to practice safer sex even if they are on therapy.

Circumcision Status

Three lines of evidence support the conclusion that circumcised men are at lower risk for HIV infection: biologic evidence, data from observational studies supported by meta-analyses, and the results of three randomized clinical trials supported by meta-analyses (Table 14–3) (Weiss et al, 2000).

Table 14–3 Evidence Table for Studies of Male Circumcision and HIV Infection Risk That Include Original Data, Systematic Reviews or Meta-Analysis, Expert Opinion, or Other Human Data (1999-2008)

The biologic mechanisms that could explain the increased risk of HIV among uncircumcised men include an increased rate of inflammatory conditions, susceptibility of the mucosal surface of the prepuce to trauma, and the longer survival of pathogens in the warm, moist subpreputial space. The inner foreskin is particularly susceptible to HIV infection owing to lack of keratinization and the high density of HIV target cells that are readily accessible (Patterson et al, 2002; Soilleux and Coleman, 2004; McCoombe and Short, 2006).

The hypothesis that male circumcision might protect against HIV infection was first suggested in 1986 (Fink, 1986). Subsequent support was provided by ecologic studies in areas with low prevalence of male circumcision and high HIV prevalence in sub-Saharan Africa in the late 1980s (Moses et al, 1999) and later across 118 developing countries (Drain et al, 2006). Further evidence comes from two systematic reviews of the observational study data comparing HIV infection rates in circumcised and uncircumcised men from the same populations (Weiss et al, 2000; Siegfried, 2005). One review was restricted to 27 studies from sub-Saharan Africa (Weiss et al, 2000), and the other was a global review including 37 studies (Siegfried, 2005). Circumcised men had substantially lower risk of HIV infection. Meta-analysis of the 15 studies that adjusted for potential confounders showed this reduction to be large and highly significant (adjusted risk ratio of 0.42, 95% CI 0.34-0.54) (Weiss et al, 2000). Subsequent studies have found similar large risk reductions among circumcised men (Weiss et al, 2008).

Although provocative, observational studies cannot prove causality. Three randomized clinical trials of adult male circumcision among consenting, healthy men in South Africa (Auvert et al, 2005), Kenya (Bailey et al, 2007), and Uganda (Gray et al, 2007) were started in 2002-2003. All three trials were stopped early after recommendations by independent data and safety monitoring boards when interim analyses found highly significant decreases in HIV infection risk among participants randomly assigned to circumcision.

The three trials enrolled a total of 10,908 uncircumcised, HIV-negative adult men. Participants were randomly assigned to circumcision or control arms and then observed for up to 2 years. Retention rates were high (86% to 92%). Subsequent meta-analysis using a random-effects model of the trial results, following the QUORUM statement recommendations, found no evidence of heterogeneity among the trials (Weiss et al, 2008). The overall risk ratio was 0.42 (95% CI 0.31-0.57), corresponding to a protective effect of 58% (95% CI 43%-69%), which was identical to that found in the observational studies (58%, 95% CI 46%-66%).

The true protection provided by male circumcision may be better estimated by an “as-treated” analysis, assigning outcomes according to the actual circumcision status of participants. All participants did not adhere to the study arm to which they were randomly assigned. Meta-analysis of the “as-treated” results of the three trials shows even stronger protection against HIV infection in the circumcision group (summary risk ratio of 0.35; 95% CI 0.24-0.54) (Weiss et al, 2008). Additional data have suggested that circumcision is both highly effective at reducing costs of HIV and AIDS and has a very low complication rate (Krieger et al, 2005, 2007; Gray et al, 2007). In summary, the positive findings in the male circumcision trials are in contrast to recent negative results with other HIV prevention interventions, including microbicides, the female diaphragm and gel, treatment to suppress genital herpes infections, and, most recently, an adenovirus-based HIV vaccine. There is a need to provide safe male circumcision services for high-risk populations because this is one of few proven HIV prevention strategies. In addition to other health benefits, male circumcision provides a much-needed addition to the limited HIV prevention armamentarium. Male circumcision is possibly the oldest and the most common surgical procedure. The evidence from biologic studies, observational studies, randomized controlled clinical trials, meta-analyses, and cost-effectiveness studies is conclusive; the challenges of implementation in high-risk populations must now be faced.

Gynecologic Factors

Female genital tract tissues vary in susceptibility to HIV infection. The stratified vaginal epithelium contains fewer cells with coreceptors that can bind HIV (Patterson et al, 1998). Thus, vaginal mucosa is less susceptible to HIV infection than the endocervix, which has a thinner, highly vascular layer, containing a much higher concentration of HIV-binding cells. Physiologic events that result in ectropion (i.e., increased exposure of the endocervix), such as the use of hormonal contraceptives or occult Chlamydia trachomatis infection, increase susceptibility to HIV (Mostad et al, 2000; Moscicki et al, 2001).

Specific Sexual Behaviors

Calculation of the precise risk for infection for each type of exposure is imprecise because many cofactors alter the amount of HIV in the genital tract (Mayer and Safren, 2004). Factors such as a source with a high plasma viral load (Quinn et al, 2000) or concomitant STI can greatly increase the average per-contact risk (Cohen et al, 1997; Wawer et al, 1999). Data used to generate per-contact risks are often based on cohort studies in which individuals recollect their risk during previous time intervals (often every 3 to 6 months). Recollections are often obtained about behaviors under the influence of drugs or alcohol.

Data from the developed world suggest that men are more likely to transmit HIV to their female partners (see Table 14–2) (Mayer and Safren, 2004). However, studies from Africa suggest that rates of male-to-female and female-to male transmission were similar (Quinn et al, 2000). Reasons for this apparent difference in the efficiency of female-to-male transmission may include different rates of male circumcision or the prevalence of other STIs. For anal intercourse the insertive partner is less likely to acquire HIV from an infected receptive partner than vice versa but there appear to be sufficient susceptible cells in the distal male urethra and foreskin such that an insertive partner is still at substantial risk. One study suggested that, on average, receptive anal intercourse was more than seven times as efficient at transmitting HIV as insertive anal intercourse (DeGruttola et al, 1989).

Oral intercourse, either fellatio or cunnilingus, is a much less efficient way to acquire HIV. However, case reports show that oral exposure to ejaculate may transmit HIV (Mayer and Safren, 2004). The efficiency of oral transmission is less than that of unprotected vaginal intercourse, in the realm of less than 1 per 1000 contacts. However, animal studies demonstrate that HIV can be transmitted orally via lymphoid tissue in the oropharynx. Although HIV has been identified in pre-ejaculatory secretions there are no reliable case reports of HIV transmission through exposure to pre-ejaculate without exposure to semen.

Viral Attachment, Fusion, and Uncoating

HIV initially attaches to the CD4 receptor on susceptible host cells. High-affinity interactions occur between the viral envelope glycoprotein and a specific region of the CD4 molecule (Pollard and Malim, 1998) on the surface of immature T cells and mature CD4+ T-helper cells. In addition to CD4, a variety of coreceptors and host immune cell membrane proteins may promote HIV entry into target cells after the initial binding (Cocchi et al, 1996; Liang and Wainberg, 2004).

Efforts are underway to develop compounds that antagonize HIV entry into susceptible cells by interfering with either the CD4 receptor or the coreceptors. Cell entry probably occurs by fusion of viral and cell membranes mediated by the viral transmembrane protein. Following fusion the virion is uncoated by a proteolytic event mediated by the virion-encoded protease. A number of protease inhibitors that inhibit this step have proven very effective antiretroviral agents.

Reverse Transcription

After entry, viral RNA is converted into DNA, which is then integrated into host cell chromosomal DNA. This process of reverse transcription occurs within 4 to 6 hours of infection and takes place mainly in the cytoplasm catalyzed by virion-encoded reverse transcriptase. The final products of reverse transcription are double-stranded viral DNA molecules. This distinctive viral reverse transcription step has been the target of a number of effective antiretroviral agents.

Integration

The newly transcribed double-stranded DNAs are then transported into the nucleus where viral DNA is integrated into host cell chromosomal DNA, a process catalyzed by viral integrase. After integration, HIV proviral DNA remains permanently associated with the host genetic material for as long as the cell lives. The viral integrase is currently under active investigation as a potential target for antiretroviral therapy.

Viral Gene Expression, Packaging, and Assembly

HIV exploits the host cell transcription and translation machineries to generate its own gene products. The primary RNA transcripts of the provirus are made by host cell RNA polymerase II. Cellular activation and proliferation signals result in the binding of transcription factors to the long terminal repeat and lead to increased rates of initiation of transcription. Tat and Rev are two key virion-encoded proteins that upregulate viral gene expression and replication, whereas HIV accessory proteins, including Nef, Vif, Vpu, and Vpr, are crucial determinants of HIV virulence (Emerman and Malim, 1998). Host cellular ribosomes translate proviral mRNA into viral proteins (Liang and Wainberg, 2004). The HIV glycosaminoglycan proteins are the driving force for virus assembly.

Therapeutic Considerations

Viral reverse transcriptase and protease enzymes have been the main targets of anti-HIV therapy. Viral reverse transcriptase has an exceedingly high error rate (i.e., about one mutation/virus replication event) (Liang and Wainberg, 2004); thus mutants are constantly generated that have the potential for drug resistance. Drug resistance to HIV occurs when these mutations result in altered forms of HIV reverse transcriptase and protease that function yet are not inhibited by antiviral agents.

Primary HIV Infection

Primary HIV infection is a transient symptomatic illness of variable severity. This acute syndrome occurs in 40% to 90% of patients. Clinical signs and symptoms generally appear 2 to 4 weeks after infection. The clinical presentation may mimic acute mononucleosis or other acute febrile illnesses, emphasizing the nonspecific nature of these symptoms and the difficulty of early diagnosis. The self-limited syndrome generally lasts less than 14 days.

Diagnosis of primary HIV infection depends on diagnostic testing. There are three laboratory characteristics: high plasma viremia often greater than 1 million HIV RNA copies/mL, a decrease in the blood CD4+ T-cell count, and large increase in the blood CD8+ T-cell count. Subsequently, a marked decline in plasma viremia coincides with resolution of the clinical syndrome (Kahn and Walker, 1998). This decrease in viral load also correlates with the appearance of the virus-specific immune responses, particularly HIV-specific cytotoxic T cells, indicating that immune responses downregulate virus replication (Pantaleo et al, 1994; Musey et al, 1997). Standard laboratory assays used to diagnose HIV infection are usually negative during acute infection.

Chronic Asymptomatic HIV Infection

Primary HIV infection is followed by a long phase of clinical latency, usually lasting around 10 years. During this phase patients have neither signs nor symptoms. Relatively stable HIV replication levels and CD4+ T-cell counts characterize this chronic phase.

This apparent clinical “stability” is deceptive. Although viral levels and the blood CD4 T-cell count are stable, this stability is only apparent in the blood. Virus replication and accumulation of extracellular virus trapped in the follicular dendritic cell network continue actively in the lymphoid tissue, where progressive anatomic and functional deterioration occurs, leading to impaired specific immune responses (Pantaleo et al, 1993, 1998). Eventually, immunologic deterioration is reflected by a rapid increase in viremia levels and a drop in CD4+ T-cell counts, resulting in transition to overt AIDS.

Overt AIDS

AIDS represents the end stage of HIV infection. This advanced stage of HIV disease is marked by low CD4+ T-cell counts (<2 to 300 cells/µL) and appearance of constitutional symptoms. This phase may be complicated by the development of AIDS-defining opportunistic infections or malignancies. Without antiretroviral therapy, AIDS usually leads to death in 2 to 3 years. The risk for death and opportunistic infections increases significantly with CD4+ T-cell counts less than 50 cells/µL.

Highly Variable Clinical Course

The clinical course of HIV infection is variable (Pierre-Alexandre and Pantaleo, 2004). Conceptually, patients may be classified in four categories: typical progressors, rapid progressors, slow progressors, or nonprogressors. In 60% to 70% of HIV-infected patients the median time between infection and the development of AIDS is 10 to 11 years, in the absence of therapy. These infected persons are “typical progressors.” Their clinical course is described earlier.

Ten to 20 percent of HIV infections progress rapidly. These “rapid progressors” develop AIDS less than 5 years after infection. After primary infection these patients’ plasma virus levels are often more than 10⁵ HIV-1 RNA copies/mL and their CD4+ T-cell counts start to decrease much earlier and more rapidly. HIV-specific immune responses are either never detected or are lost rapidly after the transition from the acute to the chronic phase of infection.

At the other extreme, 5% to 15% of HIV-infected people are “slow progressors,” remaining free of AIDS for more than 15 years in the absence of therapy. Their CD4+ T-cell counts remain stable, frequently greater than 500 cells/µL, and plasma HIV RNA levels are usually less than 10,000 copies/mL.

The slow progressors group includes a subgroup of long-term nonprogressors. About 1% of HIV-infected people appear to fall into this category. Long-term nonprogressors have documented HIV infections for at least 8 to 10 years without antiretroviral therapy and have no signs of disease progression (e.g., constant high CD4+ T-cell counts and either low [500 to 1000 HIV RNA copies/mL] or very low [<50 copies/mL] plasma virus levels).

Critical Role of Lymphoid Tissue in Primary HIV Infection

Events in the lymphoid tissue play a central role in HIV infection. During primary infection the peak number of virus-expressing cells in the lymph node occurs at the same time as the peak of plasma viremia or shortly precedes it (Brodie et al, 1999; Musey et al, 1999; Pierre-Alexandre and Pantaleo, 2004). With the transition from primary to chronic infection there is a switch from individual virus-expressing cells to virus trapped by the follicular dendritic cell network of lymph node germinal centers. This trapped virus becomes the dominant form of virus in lymph nodes, and this event is associated with a dramatic decrease in the number of individual cells expressing viral RNA, reflecting the role of the host immune system in partially containing HIV infection (Pantaleo et al, 1998).

Virus Escape and Establishment of Chronic HIV Infection

Early in primary HIV infection, vigorous virus-specific immune responses may contribute to both control of the initial peak of virus replication and reduction in plasma viremia (Musey et al, 1997; Kahn and Walker, 1998; Pantaleo et al, 1993, 1998). However, HIV-specific immune responses cannot control HIV or block the eventual progression to symptomatic disease. HIV differs from other viruses by targeting a broad spectrum of effector components of the antiviral immune response very early after infection (during the primary phase) and by rendering these mechanisms ineffective or reshaping them (Soudeyns and Pantaleo, 1999).

HIV escapes the host immune response by both virologic and immunologic mechanisms. Virologic mechanisms include formation of a stable pool of latently infected CD4+ T cells containing HIV that is capable of replicating (Finzi et al, 1997; Wong et al, 1997), the genetic variability of HIV (Coffin, 1995), and trapping of infectious virions on the surface of follicular dendritic cells (Pantaleo et al, 1994; Chun et al, 1997; Wong et al, 1997). Initiation of HAART very early during primary HIV infection does have a significant impact on the size of this pool of CD4+ T cells. Decay of this pool of infected CD4+ T cells is very slow and not much influenced by the effective suppression of virus replication. This reservoir of replication-competent virus represents a major obstacle to HIV eradication and long-term control of virus replication (Chun et al, 1997; Finzi et al, 1997; Wong et al, 1997).

Genetic variability is another efficient mechanism by which HIV escapes the host immune response. During both primary and established chronic infection, rapid mutations ensure that the virus is able to escape both the humoral and the cell-mediated virus-specific immune responses.

HIV also reshapes antiviral mechanisms by trapping of the virus on the surface of follicular dendritic cells in lymphoid germinal centers. For most infections, formation of immune complexes and their attachment to the follicular dendritic cell network represent mechanisms leading to clearance of the pathogen and to maintenance of effective immune responses. However, with HIV infection these mechanisms lead to formation of a stable reservoir of infectious virions, representing a continuous source for infection of CD4+ T cells that ultimately results in the destruction of the lymphoid tissue (Musey et al, 1997).

HIV escapes from the immune response through multiple immunologic mechanisms that include deletion of HIV-specific CD4+ T-cell clones (Rosenberg et al, 1997), deletion of HIV-specific cytotoxic CD8+ T-cell clones, generation of virus escape mutants (Soudeyns and Pantaleo, 1999), egress of cytotoxic T cells from lymph nodes, impaired function of antigen-presenting cells (Soudeyns and Pantaleo, 1999), and interference with the humoral neutralizing response.

In summary, virus escape and establishment of chronic HIV infection reflect the ability of HIV to target the host’s antiviral immune response and reshape it into a self-defense mechanism. Primary infection is critical in the pathogenesis of HIV infection because events that occur during this stage determine both the pattern and the rate of disease progression.

Virologic Set Point

During the transition from primary to chronic infection, HIV plasma RNA levels reach a virologic set point that predicts the rate of disease progression (Mellors et al, 1996). The virologic set point varies among HIV-infected individuals and tends to remain stable in the same person during the chronic phase. The virologic set point that a person attains is determined by both the mechanisms involved in the establishment of chronic infection and by host factors that can modulate the course of HIV disease. The plasma RNA load is the most accurate predictor of disease progression (Mellors et al, 1996). The higher the plasma viral RNA load, the greater is the risk of rapid progression to AIDS and death.

Clinical Application

After acute infection, HIV RNA can be detected from day 12. HIV RNA assays (see later) have a sensitivity of 100% in diagnosing acute infection but at the cost of lowered specificity (97%) (Kuritzkes, 2004). The first antibodies can generally be detected on day 21. However, development of a positive HIV antibody test can vary according to the patient and infecting strain. Beyond week 6 after infection antibodies are detectable in almost all patients (Kuritzkes, 2004). Because reactivity by the Western blot test lags seroconversion by ELISA, a positive ELISA in a patient with a negative or evolving Western blot assay can provide evidence of recent infection.

Testing is a two-stage process. Samples positive by an initial screening assay are retested to exclude clerical or laboratory error, and then a confirmatory assay is performed on repeatedly reactive sera to verify that the antibodies are directed against HIV. Confirmation of a reactive ELISA by a positive Western blot establishes the diagnosis of HIV infection. A negative Western blot test suggests a false-positive ELISA or an acute infection.

Clinical Application

Plasma HIV RNA levels correlate with clinical stage (Kuritzkes, 2004). Patients with symptomatic HIV infection or AIDS have significantly higher virus loads than patients with asymptomatic infection. Plasma HIV RNA load is also a powerful predictor of the risk of disease progression and death at all stages of disease. Current guidelines recommend obtaining two plasma HIV RNA measurements to determine the baseline or “set point” virus load before initiating antiretroviral therapy.

After antiretroviral therapy the change in plasma HIV RNA provides important clinical information. Several large clinical trials showed significant correlations between the plasma HIV RNA reduction from baseline and the clinical benefit (Marschner et al, 1998). The nadir in plasma HIV RNA levels is a marker for the duration of virus suppression (Raboud et al, 1999). The early response to treatment predicts long-term outcome. Conversely, increasing plasma HIV RNA level suggests treatment failure.

Increasing plasma HIV RNA level is the harbinger of potential development of retroviral drug resistance (Reiss et al, 2004). This is not necessarily accompanied by an immediate decline in blood CD4+ lymphocyte numbers or by the development of clinical symptoms. Regular monitoring with plasma HIV RNA levels facilitates timely detection of drug-resistant HIV in patients on HAART.

Clinical Application

Clinical trials demonstrate the value of drug-resistance testing (Kuritzkes, 2004; Reiss et al, 2004). The risk of virologic failure during salvage therapy was reduced by 30% to 50% for each drug in the new regimen that was predicted to have activity (De Gruttola et al, 2001; Kuritzkes, 2004). Drug-resistance remained an independent predictor of the likelihood of treatment failure even after controlling for treatment history.

Most experts recommend drug-resistance testing to guide the selection of salvage therapy for patients whose therapy is failing and in pregnant women (Hirsch et al, 2000). Resistance testing is also recommended for patients with acute HIV infection. Some experts also recommend that evidence for increasing transmission of drug-resistant HIV (Little et al, 2002) provides a rationale for testing of all patients before initiation of antiretroviral therapy where affordable (Kuritzkes, 2004).

Primary HIV Infection

Primary HIV infection may be characterized by an acute exanthem beginning 1 to 5 weeks after infection. Characteristic symptoms include fatigue, fever, and night sweats, accompanied by lymphadenopathy. The skin eruption consists of erythematous, round-to-oval macules and papules. The syndrome resolves with complete recovery.

Sexually Transmitted Infections

In many populations the pattern of HIV acquisition parallels that of STIs (Quinn et al, 1988). Thus, testing for HIV is recommended in anyone with a diagnosed STI or at risk for STI (Centers for Disease Control and Prevention, 2002). Accurate diagnosis of STIs is of exceptional importance in individuals at high risk for HIV infection because presence of an STI increases the risk of both transmitting and acquiring HIV infection. These infections may have more atypical and prolonged clinical manifestations in people with HIV infection.

Genital Herpesvirus

Herpes simplex virus (HSV) infection is common in HIV-infected persons (Centers for Disease Control and Prevention, 2002

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