I.  EPIDEMIOLOGY AND NATURAL HISTORY OF
HIV INFECTION IN WOMEN
Ruth M. Greenblatt, MD, and Nancy A. Hessol, MSPH

I. INTRODUCTION

The successful introduction and spread of the human immunodeficiency virus (HIV) into the global human population has occurred for many reasons. The discovery and widespread use of penicillin and other antibiotics meant that there was treatment and cure for most sexually transmitted diseases. The existence of these new drugs changed how people perceived risks associated with sexual activity. Soldiers in World War II increasingly used prophylactics, and the subsequent development of hormonal contraceptives hastened the pace of change in sexual practices, as prevention of pregnancy became a real possibility. Lifestyles also were changing: people were moving into regions that were previously uninhabited by man and long-distance travel became easier and was much more common, allowing for more social migration and sexual mixing. Although the virus may have been first introduced to humans earlier in the 20th century (most likely contracted from infected animals), it was in the 1970s that wider dissemination occurred.

     For industrialized countries, the first evidence of the AIDS epidemic was among groups of individuals who shared a common exposure risk. In the United States, sexually active homosexual men were among the first to present with manifestations of HIV disease, followed by recipients of blood or blood products, then injection drug users, and ultimately children of mothers at risk. Women have represented an increasing proportion of reported AIDS cases in the United States, accounting for 23% of adult cases from July 1998 to June 1999 (CDC, 1999). Eighty percent of AIDS cases in women are in African Americans and Hispanics, as compared with 61% of cases in men.

     In developing countries, the AIDS epidemic manifested itself quite differently, both because the signs and symptoms were harder to identify because of other competing causes of morbidity and mortality and because the epidemic did not seem to be limited to “high-risk” groups and, instead, was more generalized. Worldwide, women now represent 43% of all adults living with HIV and AIDS (Table 1-1), and this proportion had been steadily increasing over time (UNAIDS, 1998).

     This chapter reviews the epidemiology of HIV/AIDS, beginning with how HIV is transmitted and the variables involved; the natural history of HIV infection in women — both without treatment and in the era of highly active antiretroviral therapy (HAART), and concluding with future issues regarding the HIV/AIDS epidemic.

A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV
Epidemiology and Natural History of HIV Infection in Women

I

II. HIV TRANSMISSION

Epidemiologic studies have demonstrated that HIV is transmitted by three primary routes: sexual, parenteral (blood-borne), and perinatal. Virtually all cases of HIV transmission can be attributed to these exposure categories. Transmission rates from the infected host to the uninfected recipient vary by both mode of transmission and the specific circumstances. Because HIV is a relatively large virus, has a short half-life in vitro, and can only live in primates, HIV cannot be transmitted from causal (i.e., hugging or shaking hands) or surface (i.e., toilet seats) contact or from insect bites.

A. MODES OF TRANSMISSION

Sexual transmission of HIV from an infected partner to an uninfected partner can occur through male-to-female, female-to-male, male-to-male, and female-to-female sexual contact. Worldwide, sexual transmission of HIV is the predominant mode of transmission (Quinn, 1996). Among U.S. women with AIDS, sexual transmission constitutes 40% of reported cases as of June 1999 (CDC, 1999). This 40% is probably an underestimate when you take into consideration that a large proportion of the women with AIDS who report no identifiable risk (an additional 15% of AIDS cases in women) are actually also infected via sexual transmission. While receptive rectal and vaginal intercourse appear to present the greatest risk of infection (approximately 0.1–3% and 0.1–0.2%, respectively, per episode), insertive intercourse (both rectal and vaginal) has also been associated with HIV infection (approximately 0.06% and 0.1%, respectively, per episode) (Mastro, 1996; Vittinghoff, 1999). In addition, there have been a few case reports of male-to-male transmission from receptive oral intercourse with an HIV-infected male partner (approximately 0.04% per contact) (Lifson, 1990; Samuel, 1993; Vittinghoff, 1999) and female-to-female transmission from oral-vaginal, oral-anal, and digital intercourse (Marmor, 1986; Monini, 1996; Monzon, 1987; Perry, 1989; Rich, 1993; Sabatini, 1983).

     Parenteral transmission of HIV has occurred in recipients of blood and blood products, through transfusion of blood (estimated 95% risk of infection from transfusion of a single unit of HIV-infected whole blood [CDC, 1998a]) or clotting factors, in intravenous or injection drug users through the sharing of needles (approximately 0.67% risk per exposure [Kaplan, 1992]), in health care workers through needlesticks (approximately 0.4% risk per exposure, depending on the size and location of the inoculum [Tokars, 1993]), and, less commonly, mucous membrane exposure (Hessol, 1989). Among cumulatively reported AIDS cases in U.S. women through June 1999, 42% had injection drug use as their exposure risk and 3% receipt of blood, blood products, or tissue (CDC, 1999). Parenteral transmission patterns vary by geographic region due to social and economic factors. For instance, in regions where the prevalence of HIV infection is higher, the risk of occupational or nosocomial transmission of HIV is greater than in regions where there is lower prevalence (Consten, 1995). The transmission risk is therefore related to the prevalence of HIV in the population as well as the frequency of exposure to infected body fluids and organs and the method of exposure (Fraser, 1995). In addition, many developing countries that have a high prevalence of HIV infection also lack the resources to implement universal precautions adequately (Gilks, 1998) and may experience a greater amount of transfusion-associated HIV transmission due to a lack of HIV antibody screening in some areas, a higher residual risk of contamination in blood supplies despite antibody screening (McFar-land, 1997), and high rates of transfusion in some groups of patients.

     Perinatal transmission can occur in utero, during labor and delivery, or post-partum through breast-feeding (Gwinn, 1996). Perinatal transmission rates average 25–30% (Blanche, 1989), but vary by maternal stage of disease, use of antiviral therapy, duration of ruptured membranes, practice of breast-feeding, and other factors. In the United States as of June 1999, 91% of cumulative pediatric AIDS cases were attributed to perinatal transmission (CDC, 1999). More information on perinatal transmission can be found in Chapter VII on HIV and Reproduction.

B. FACTORS FACILITATING TRANSMISSION

Transmission of HIV infection can be influenced by several factors, including characteristics of the HIV-infected host, the recipient, and the quantity and infectivity of the virus. A summary of factors affecting sexual transmission of HIV is presented in Table 1-2.

INFECTIOUSNESS OF THE HOST

There is an association between the quantity of virus transmitted and the risk of HIV infection (Roques, 1993). Several studies have found that HIV-infected persons may be more likely to transmit the infection when viral replication is high, both during the initial stage of infection (Palasanthiran, 1993) and at more advanced stages of HIV disease (Laga, 1989). People with high blood viral load are more likely to transmit HIV to recipients of blood, their sexual partners, and their offspring (Quinn, 2000; Vernazza, 1999). HIV has been quantified in semen (Coombs, 1998; Speck, 1999; Vernazza, 1997) and detected in female genital secretions (Ghys, 1997; Mostad, 1998), and virus in these locations may facilitate transmission. However, the association between infectivity and disease stage is not absolute; HIV-infected women may transmit virus to a first-born child but not to a second-born child (de Martino, 1991), and temporal studies of semen from HIV-infected men demonstrate waxing and waning viral titers over time (Krieger, 1991; Tindall, 1992).

    A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV Epidemiology and Natural History of HIV Infection in Women

TABLE 1-2: BIOLOGIC AND HOST-RELATED FACTORS AFFECTING SEXUAL                        TRANSMISSION OF HIV
	HOST-RELATED INFECTIVITY FACTORS
	HIV CONCENTRATION	INFECTIOUSNESS	SUSCEPTIBILITY
BIOLOGIC FACTOR	IN GENITAL SECRETIONS	(TRANSMISSION)	(ACQUISITION)
Mutation of chemokine- receptor gene	?	?
Late stage of HIV infection			Not applicable
Primary HIV infection			Not applicable
Anti-retroviral therapy			?
Local infection
Presence of cervical ectopy?		?
Presence of foreskin?	?
Method of contraception
Barrier	Not applicable
Hormonal contraceptives		?
Spermicidal agents	?	?
Intrauterine devices	?	?
Menstration	?
Factors that lower cervicovaginal pH?	?	?	?
Immune activation	?
Genital tract trauma?	?
Pregnancy		?	?

The degrees of positivity (to ) and negativity (to ) of the associations are indicated with arrows, with three arrows indicating a very strong association. The symboldenotes that there is evidence in support of both a positive and negative association. A question mark (s) indicates an unknown or hypothesized association that is not currently supported by data.
Source: Royce, 1997.

     Factors that decrease viral titers, including antiretroviral therapy, may decrease but not eliminate the risk of HIV transmission (Hamed, 1993). Zidovudine has been shown to reduce vertical transmission from mothers to their fetus even when administered late in pregnancy or during labor (CDC, 1998b). (See Chapter VII on HIV and Reproduction.) Individuals receiving antiretroviral therapy have also shown reduced rates of HIV transmission to their sex partners (Musicco, 1994). Several studies have suggested that anti-retroviral treatment reduces detection of HIV in female genital secretions (Cu Uvin, 1998) and the concentration of HIV in semen (Gilliam, 1997; Gupta, 1997). Providers counseling patients on treatment should be clear that precautions to prevent transmission of the virus should be maintained because not all treatments reduce infectiousness, and transmissions have been reported among individuals with undetectable HIV RNA levels (European Collaborative Study Group, 1999).

     Factors that increase the risk of exposure to blood, such as genital ulcer disease (Cameron, 1989; Plummer, 1991), trauma during sexual contact (Marmor, 1986), and menstruation of an HIV-infected woman during sexual contact (European Study Group, 1992; Nair, 1993; St. Louis, 1993) may all increase the risk of transmission.

     Method of contraception also affects the likelihood of HIV transmission (Daly, 1994). There is overwhelming evidence that the correct and consistent use of latex condoms protects both men and women against HIV. However, because of methodologic difficulties in studies of contraceptive use and HIV transmission, it remains unclear whether the use of hormonal contraceptives, IUDs, and spermicides alters the risk of HIV transmission.

SUSCEPTIBILITY OF THE RECIPIENT

Similarly, characteristics of the uninfected individual may increase the likelihood of infection for a given exposure to HIV. Specifically, inflammation or disruption of the genital or rectal mucosa (which can occur with sexually transmitted diseases and trauma) and lack of circumcision in heterosexual men may increase the risk of infection (Cameron, 1989; Moses, 1994; Quinn, 2000). Sex during menstruation may increase women’s risk of acquiring HIV infection (Lazzarin, 1991) as may bleeding during sexual intercourse (Seidlin, 1993). In women, both ulcerative and nonulcerative sexually transmitted diseases have been shown to be risk factors for getting infected with HIV (Laga, 1993; Plummer, 1991). Cervical ectopy has been identified as a risk factor for acquisition of HIV infection in some (Nicolosi, 1994; Plourde, 1994) but not all (Mati, 1994) studies that have evaluated this condition. There is also some evidence that changes in the vaginal flora, as characterized by bacterial vagi-nosis, may facilitate acquisition of HIV (Sewankambo, 1997).

     Nonbarrier contraceptive methods have also been investigated in association with risk of HIV transmission but the results are inconclusive. The most frequently studied methods of contraception have been oral contraceptives, injectable hormones, intrauterine devices, and nonoxynol-9 (Daly, 1994; Plum-mer, 1998). (See Chapter III on Prevention of HIV.) Traditional vaginal agents, used in African women for sexual enhancement and self-treatment of vaginal symptoms, have also been investigated as potential cofactors for HIV transmission (Dallabetta, 1995). For many of these studies, limitations of the study design preclude any definitive conclusions.

     There is increasing evidence that host genetic or immunologic factors may protect against HIV infection. This has been investigated in cohort studies of Nairobi sex workers (Willerford, 1993) and U.S. homosexual men (Dean, 1996), in which both sets of study subjects remained uninfected despite multiple sexual exposures to HIV. Individuals who are homozygous for a null allele of CCR5 are relatively resistant to sexually transmitted infection with HIV, indicating an important, though not absolute, role for this receptor in viral transmission. However, homozygous CCR5 mutations were not found among 14 hemophiliacs who remained uninfected with HIV after being inoculated repeatedly with HIV-contaminated Factor VIII concentrate from plasma during 1980–1985 (Zagury, 1998). In this study, investigators found an overproduction of ß-chemokines in most of the uninfected individuals.

VIRAL PROPERTIES

Several viral factors have been proposed to play a role in the transmissibility of HIV. These include phenotypic characteristics (e.g., envelope proteins required for transmission), genetic factors that control the replicative capacity and “fitness” of the virus, and resistance to antiviral drugs (Vernazza, 1999).

     Envelope sequences can define viral quasispecies that have been phenotypically arranged according to their ability to induce syncytia formation in infected T-cells (Paxton, 1998). It appears that the most commonly transmitted phenotype is the nonsyncytia-inducing, M-tropic viral strain, which is frequently found in those who have been recently infected. During the course of HIV infection the development of a more cytopathic, syncytia-inducing, T-tropic viral phenotype can be found and this is often a precursor to the development of AIDS. While some researchers have suggested that nonsyncytia-inducing isolates of HIV are preferentially transmitted (Roos, 1992), others have not been able to show preferential transmission of this isolate (Albert, 1995).

     Envelope sequences can also be used to define viral subtypes, or clades, and these subtypes may also influence the transmissibility of HIV. The distribution of HIV subtypes differs according to geographic region, with A, C, D, and E predominant in Sub-Saharan Africa and Asia and B predominant in the United States, the Caribbean, South America, and Western Europe (Hu, 1996). In one study, subtype E is reported to have greater tropism for Langerhans cells than subtype B (Soto-Ramirez, 1996) and may have a greater per-contact transmissibility.

     The transmission characteristics of a viral strain that is resistant to certain antiretroviral agents may differ from transmission of wild-type virus. More research is needed in this emerging field of therapy-resistant virus and its characteristics.

III. NATURAL HISTORY AND HIV DISEASE PROGRESSION

The natural history of HIV infection in adults has been extensively documented in the medical literature. The impact of gender on the manifestations and progression of HIV disease is still being investigated. Concerns about gender-based differences in the course of HIV infection were expressed early in the epidemic. In most industrialized countries, women tended to have lower income, be un- or underinsured for health care, know less about HIV, more likely to be Black or Hispanic, and to have a personal or partner history of injection drug or cocaine use. Women also appeared to have more rapid progression of illness than men and to present with a different constellation of opportunistic conditions than men. When sophisticated statistical methods were applied that controlled for the tendency of women to receive less care and to present with more advanced disease, gender-based differences in HIV disease course appeared to lessen. More recently, however, with better measures of viral activity and infirmity, the issue of gender-based differences in rate of disease course and virologic parameters has again been raised. These new observations have prompted active research into the impact of gender, hormones, and demographic factors on the outcome of HIV infection.

     HIV infects and induces cell death in a variety of human cell lines. T-helper lymphocytes (also known as CD4 cells) are a major target of viral infection, and circulating CD4 cells become steadily depleted from peripheral blood in most untreated infected persons. Thus quantification of CD4 cells in blood is a rather simple way of determining cumulative immunologic damage due to HIV. Profound CD4 cell depletion is unusual in persons who do not have HIV infection and is usually iatrogenic or associated with severe illnesses, such as chemotherapy-induced leukopenia (Aldrich, 2000). Other immunologic parameters become altered with HIV disease progression, and though often used for research purposes, they tend to be more difficult to measure and less reliable or more costly.

     Untreated HIV infection is a chronic illness that progresses through characteristic clinical stages; AIDS is an endpoint of HIV infection, resulting from severe immunologic damage, loss of an effective immune response to specific opportunistic pathogens and tumors. AIDS is diagnosed by the occurrence of these specific infections and cancers or by CD4 cell depletion to less than 200/mm3.

A. STAGING

HIV can cause a wide range of symptoms and clinical conditions that reflect varying levels of immunologic injury and different predisposing factors. Certain conditions tend to occur in association with each other and at specific CD4 cell counts. Staging systems for HIV disease facilitate clinical evaluation and planning therapeutic interventions, help determine the individual level of infirmity, and give prognostic information. Untreated HIV infection is a chronic illness that progresses through characteristic clinical stages that can be used to describe infirmity. Several groups have produced organized staging systems to facilitate clinical evaluation and planning therapeutic interventions. In industrialized countries, the most widely used system for classifying HIV infection and AIDS in adults and adolescents was published by the United States Centers for Disease Control and Prevention in 1993 (CDC, 1992).

     The case definition (Table 1-3) begins first with confirmation of HIV infection either via serologic testing (combination of a screening method such as enzyme immunoassay and more specific confirmatory test such as Western blot), or direct detection of HIV in patient tissue by viral culture, antigen detection, or other test such as polymerase chain reaction (PCR). The definition of each stage of illness is then based on two types of information: peripheral blood CD4 cell counts and clinical manifestations. CD4 cell counts are placed in three strata, ranging from relatively normal (>500 cells/mm3) to severe CD4 depletion (<200 cells/mm3).

     The clinical manifestations of HIV infection are also placed in three strata, generally in accordance with the level of immunologic dysfunction associated with the various conditions (Table 1-3). Category A includes persons who have minimal clinical findings, clinical findings that do not indicate immune injury (including absence of symptoms), generalized lymphadenopathy, or resolved acute HIV infection. Category B includes conditions that indicate the presence of a defect in cell-mediated immunity or conditions that appear to be worsened by HIV infection. Category C includes conditions that are considered AIDS defining, even in the absence of a CD4 cell count less than 200 cells/mm3 (CDC, 1992). The addition of specific laboratory measures, such as plasma HIV RNA level, improves prognostic value even after the occurrence of Category C conditions (Lyles, 1999).

DEVELOPING WORLD

The CDC criteria require diagnostic testing and case confirmation methods that may not be available in developing countries, so several other sets of criteria have been proposed for these regions. Because lymphocyte subset quantitation is not widely available in many countries, the Global Program on AIDS of the World Health Organization (W.H.O.) proposed a clinically based staging system that is more broadly applicable than the CDC system (W.H.O., 1993). The system uses clinical historical data, laboratory measures (optional), and indices of physical activity to assess level of infirmity to establish four clinical stages, summarized in Table 1-4. Laboratory measures include a single-assessment absolute CD4 cell count, with the option of replacing this test with total lymphocyte count, both of which are placed in three strata. CD4 cell count is a better prognostic indicator than total lymphocyte count, but the two results correlate well (Brettle, 1993).

     Clinical history and functional measures are placed in four categories that range from asymptomatic to severe disease. In general, when compared with the CDC stages, the W.H.O. system requires fewer diagnostic test data and fewer direct observations. The definition includes broader categories for conditions that may vary by region (e.g., disseminated infections with endemic mycoses, which are common in Southeast Asian AIDS patients but not in the United States or Europe). The inclusion of performance scale measures permits quantitative clinical assessment that is not dependent on laboratory resources.

     The four clinical stages in the W.H.O. system correlated well with CD4 cell counts and HIV RNA levels in a study of 750 Ethiopians (including 336 women) by Kassa and others (Kassa, 1999). Other studies of patient populations have also demonstrated correlation of W.H.O. clinical stage with CD4 cell count and clinical outcome (Morgan, 1997; Morgan, 1998; Schechter, 1995). When compared with the CDC staging, the W.H.O. clinical stages demonstrated a high degree of specificity, but a lower level of sensitivity (35–65%) for HIV infection (Gallant, 1992; 1993). In particular all of the systems for disease staging are not perfectly sensitive and specific for HIV infection, but can be improved by the addition of HIV serologies (Ankrah, 1994; De Cock, 1991). Modifications (Table 1-4) have been proposed that improve the prognostic accuracy of the W.H.O. system. Based on observations made in a study of AIDS mortality among Rwandan women, Lifson and colleagues proposed minor modifications of clinical history definitions, replacement of body mass index (weight[kg] divided by height [m2]) for weight loss and use of erythrocyte sedimentation rate as a laboratory indicator of infirmity (Lifson, 1995). Body mass index was significantly better at predicting mortality than percentage of body weight lost over two measurements taken in 1 yr. Both erythrocyte sedimentation rate and hematocrit were highly predictive of mortality over a 36-mo period of observation (Lifson, 1995).

     Other HIV-disease classifications, such as the Caracas definition proposed by the Pan American Health Organization (Rabeneck, 1996; Weniger, 1992), have been proposed but have not been evaluated as extensively as the CDC and W.H.O. systems.

B. UNTREATED NATURAL HISTORY

PRIMARY OR ACUTE INFECTION

Acute HIV infection is a transient symptomatic illness that can be identified in 40–90% of cases of new HIV infection. It is characterized by a high rate of HIV replication, high titers of virus in blood and lymphoid organs (up to several million copies of HIV RNA per cubic millimeter of plasma), and initiation of an HIV-specific immune response. The amount of virus present in blood and tissues begins to fall after the appearance of cytotoxic (“killer”) lymphocytes that specifically react with HIV antigens; the vigor of this response varies among individuals and is associated with subsequent rate of disease progression (Cao, 1995). A pool of persistently infected CD4 cells (“latent reservoirs”) emerges early in the course of HIV infection and persists indefinitely (Chun, 1998).

     Symptoms have been identified 5–30 days after a recognized exposure to HIV (Schacker, 1998). The signs and symptoms of acute HIV infection are not specific; fever, fatigue, rash, headache, lymphadenopathy, pharyngitis, mild gastrointestinal upset, night sweats, aseptic meningitis, and oral ulcerations are most frequently reported. Because the clinical signs of acute HIV infection resemble those of many acute viral illnesses, the correct diagnosis is often missed. Because early treatment at the time of acute infection may be especially beneficial (see Chapter IV on Primary Medical Care), early suspicion of and evaluation for HIV infection should be encouraged (Kahn, 1998).

ESTABLISHED INFECTION

Regardless of whether the syndrome of acute HIV infection is recognized or not, after the HIV-specific immunological response begins to control the intensity of viremia, a so-called “viral set point” is established, which varies by individual. With exceedingly rare exceptions, the immunological response to HIV does not eliminate infection, but rather establishes a steady state between viral replication and elimination (Henrad, 1995). A variable level of viremia is attained that can be measured via quantification of the number of copies of HIV RNA present in blood (viral load). Although the viral load within the first 120 days of HIV infection is not of prognostic value (Schacker, 1998), most patients establish a relatively stable viral load after recovering from acute infection, and this viral set point is highly predictive of the rate of future progression of illness, at least as determined in studies that focused largely on men. In the case of a high viral load set point (i.e., values ranging up from 40,000 copies/mm3), more rapid decline in CD4 cell counts and more rapid occurrence of Clinical Class B and C conditions will occur. Some patients have low viral load set points (below 500 copies/mm3), which indicates a better prognosis; no evidence of progression (CD4 cell depletion or HIV diseases) is seen for long periods of time in a small subset of patients (see section on long-term progression, below). The viral set point is likely influenced by several factors such as presence of other infections at the time of HIV exposure, genetic characteristics (particularly the type of HIV binding receptors present on lymphocytes), viral characteristics, age, and perhaps gender (see below) (Kahn, 1998).

     During the period of clinical stability, acute illnesses and other events that can stimulate the immune system, such as influenza, herpes simplex outbreaks, tuberculosis, and even routine vaccinations, have been demonstrated to result in 10–1000-fold increases in viral load; these increases are transient and most often resolve within 2 months (Stanley, 1996; Staprans, 1995). Thus, determination of viral load for prognostic purposes should not be done during or shortly after an acute illness.

     For most HIV-infected persons, viral quasispecies evolve overtime. Transition for the nonsyncytia-inducing macrophage-tropic viral strains that are commonly present after transmission to syncytia-inducing T-lymphocyte tropic strains occurs in many hosts. While variation of viral quasispecies with time is usual, the mechanism by which this process occurs has not been defined. However, transitions in viral quasispecies and cellular tropism have been observed to coincide with key clinical events such as CD4 cell depletion and development of symptomatic illness. These virologic changes may reflect evolution of a virus that is tailored to an individual’s immune response or other genetic characteristics. Interventions that prevent evolution of quasispecies in a host may yield effective therapies in the future.

     The HIV RNA level in tissues does not correlate in a linear fashion with blood levels, so even in patients with undetectable plasma HIV RNA, intracel-lular and tissue HIV RNA can still be detected with more sophisticated techniques (Hockett, 1999). Thus HIV replication continues at varying pace among infected persons, even those who can control viremia well.

     HIV is also frequently present in the genital tract (Fiore, 1999; Iversen, 1998), where expression of inflammatory mediators and lymphocyte receptors differ from blood and may influence the rate of viral replication and numbers of virions present (Anderson, 1998; Hladik, 1999). While the quantities of HIV present in cervicovaginal fluid are generally similar to those in blood (Hart, 1999; Shaheen, 1999), they differ in some individuals. The finding that HIV isolates from the lower genital tract can have different genotypic markers than blood isolates from a single host (Di Stefano, 1999; Shaheen, 1999) supports the concept that the lower genital tract sometimes functions as a separate virologic compartment.

TIME COURSE

In most studies of seroconverters (persons for whom the date of the HIV infection can be estimated), 50–60% of adults will be diagnosed with an AIDS-defining condition within 10 years of infection (for the pre-HAART treatment era). Forty-eight percent of seroconverters die (due to any cause) after 10 years of infection. Increasing age is the factor most consistently associated with rate of progression and death in most groups of patients studied to date (Alioum, 1998; UK Register of HIV Seroconverters Steering Committee, 1998; Pezzotti, 1999b; Prins, 1999). Date of infection also influences time from infection to an AIDS diagnosis, at least in some locations, demonstrating that even in the pre-HAART era, improvements in treatment resulted in tangible benefits (Webber, 1998).

LABORATORY INDICATORS AND PREDICTORS

A large number of laboratory tests have been evaluated as prognostic indicators in HIV infection. For the most part, the tests can be divided into three groups: A, measures of HIV replication; B, measures of immune function; and C, measures of inflammation. Group A is specific to HIV infection; Group B, when indicating severe CD4 cell depletion, is relatively specific to HIV infection; and Group C is generally not specific to HIV infection. Table 1-5 summarizes these laboratory measures, their outcomes, and their advantages and disadvantages. HIV RNA quantitation, performed on fresh or fresh-frozen plasma or serum, is a powerful and accurate prognostic indicator in HIV infection and is uniquely useful in determining response to antiretroviral therapy (Saag, 1996). In general the best measures of prognosis and staging include combinations of HIV RNA level, CD4 cell count, and perhaps lymphocyte function (cytotoxic lymphocyte response to HIV) (Spijkerman, 1997; Vlahov, 1998). 

LONG-TERM NONPROGRESSORS

In untreated adults the median time from HIV infection to AIDS in developed countries is 8-10 years. However, approximately 8-15% of HIVinfected persons (most studies focus on men) remain symptom free for much longer periods of time (Buchbinder, 1994; Munoz, 1995), a phenomenon that has been named long-term survival (LTS). Among these individuals who remain clinically stable without treatment for 5�8 years, two groups can be discerned, those who have stable CD4 cell counts and those who have low CD4 cell counts but no AIDS-defining conditions (Schrager, 1994). Several factors have been found to be associated with longterm survival including host characteristics such as the presence of specific anti-HIV cytotoxic lymphocyte responses and viral characteristics such as defective genes and gene products (Kirchhoff, 1995). LTS patients tend to have consistently lower levels of HIV RNA after the period of acute infection, suggesting better control of viral replication (Vesanen, 1996). For example, viral growth in peripheral mononuclear cells taken from LTS patients was markedly less than in perhipheral blood mononuclear cells taken from healthy HIVuninfected donors (Cao, 1995).

GENDER EFFECTS

In general the predictors of the rate of HIV disease progression and survival among women are the same as in men. CD4 cell count depletion and higher HIV RNA level are strong predictors of progression and survival in women (Anastos, 1999b). Several recent reports, however, describe genderbased differences in HIV RNA level and in rate of CD4 cell depletion; women had HIV RNA levels 30-50% lower than men who had comparable CD4 cell counts (Bush, 1996; Evans, 1997; Farzadegan, 1998). Similar results occurred when analysis was restricted to seroconverters or when HIV culture was used to quantify viremia rather than RNA assays (Lyles, 1998; Sterling, 1999). Intuitively, lower levels of circulating HIV RNA, which suggest lower steady-state levels of viremia, should be associated with better outcome. However, several recent studies suggest that the lower HIV RNA level does not provide benefit to women. Women experienced more rapid CD4 cell depletion and faster progression to AIDS and death than men at similar HIV RNA levels, even when race and age were taken into consideration (Anastos, 1999a; Farzadegan, 1998).

Determination of the effect of gender on the rate of progression, time until occurrence of an AIDS-defining condition, and death is a complicated process. Unless the date of HIV infection can be established, duration of infection becomes a significant unknown factor in studies. In addition, particularly in developed countries, HIVinfected women and men differ by more than just their gender. Women tend to have lower income, be members of minority ethnic groups, have been born in Africa, have used injection drugs or cocaine, or to have a sexual partner who has done so, all of which are risk factors for poor health in general. In most studies women have shorter duration of infection prior to AIDS and death than men, but these differences tend to disappear when CD4 cell count and drug use are taken into consideration (Alioum, 1998; UK Register of HIV Seroconverters Steering Committee, 1998; Pezzotti, 1999a; Santoro-Lopes, 1998). Several studies have reported an excess proportion of infections or deaths due to bacterial infection, often pneumonia (Feld-man, 1999), among women compared with men (Melnick, 1994; Weisser, 1998).

C. NATURAL HISTORY IN HAART ERA

INDUSTRIALIZED COUNTRIES

In countries that are able to provide highly active antiretroviral therapy (HAART), HIV-associated morbidity and mortality have declined significantly (Michaels, 1998; Miller, 1999a; Miller 1999b; Palella, 1998; Pezzotti, 1999b). (See Primary Medical Care in Chapter IV for more information.) These population findings, based on regional surveillance systems, were preceded by a multitude of clinical trials that demonstrated clinical and virologic benefits of HAART (Bartlett, 1996; Collier, 1996; Deeks, 1997; Hammer, 1997). Despite the promise and documented benefits of HAART, clinical progression continues to occur among recipients, particularly among persons who received antiretroviral treatment before initiation of HAART (Ledergerber, 1999). Viral resistance to HAART components can occur via several mechanisms, which for the most part involve mutation of viral target proteins (Richman, 1996; Schapiro, 1999). The emergence of antiretroviral resistance is a function of several factors: prior treatment, pre-treatment level of viremia, drug levels (adherence to medication regimens, bioavailability of medications, adequate dosing), and specifics of the regimen (Gulick, 1998; Ledergerber, 1999; Shafer, 1998). Multiple daily doses, side effects, and, in some cases, dietary restrictions aggravate the problem of achieving optimal drug levels because protease inhibitor agents are relatively poorly bioavailable. Suppression of viral replication and prevention of resistance are directly related to level of antiretroviral drug. Persistent viral replication provides an opportunity for resistant mutations to occur, and selective pressure to support the continued presence of such mutants (Condra, 1998; Feinberg, 1997; Wong, 1997). Besides clinical treatment failure, emergence of antiretroviral resistance is now associated with transmission of resistant virus to previously uninfected persons, a finding that could portend significant limits to the effectiveness of these treatments in populations over long periods of time (Boden, 1999; Brodine, 1999; Yerly, 1999).

DEVELOPING COUNTRIES

The high cost of antiretroviral drugs and the need for clinical and laboratory services for monitoring response to and efficacy of these treatments has greatly restricted provision of HAART in the developing world. Thus the reductions in morbidity and gains in survival in HIV patients that have been demonstrated in many industrialized countries do not extend to developing countries in which the majority of HIV cases worldwide occur. A consensus statement regarding provision of these therapies has been released based on meetings held in Dakar and Abidjan during 1997. The key recommendations of conference participants include: efforts must be made to expand provision of antiretroviral therapy, antiretroviral therapy only makes sense in the setting of effective AIDS control programs, funding must be sustained to provide uninterrupted treatment and continuity of care, care providers must be trained in use of the treatments and basic patient rights, resources for assessment of efficacy and tolerance must be available, sentinel monitoring for resistance pattern determination should be available, 3-drug combination regimens should be used when possible, treatment of pregnant women to prevent perinatal transmission must be a priority, and new drug development should focus on less costly medications (International AIDS Society, 1999).

A. GLOBAL IMPACT

The HIV/AIDS epidemic continues to spread without full control in any country. Over 40 million people have been infected worldwide. By the end of 1998, the United Nations Program on AIDS (UNAIDS) estimated that 33.4 million people were living with HIV, a figure that includes 13.8 million adult women (UNAIDS, 1998) (Table 1-1). In 1998 it is estimated that 5.8 million new HIV infections occurred, with 2.1 million of these occurring in women. After steady increases of the prevalence of disease among women during the 1990s, currently 43% of all persons over the age of 15 living with HIV are women. Globally, AIDS is now the fourth leading cause of mortality; 2.5 million deaths have been attributable to AIDS, of which 900,000 occurred in women. The notable improvements in AIDS mortality reported in North America and Europe, in association with the introduction of highly active combination anti-retroviral therapies, do not extend to most of the world’s cases, which occur in regions where this expensive type of treatment is not available.

     More than 95% of HIV-infected people live in the developing world, most in Sub-Saharan Africa. Seventy percent of infections that occurred during 1998 took place in this epicenter. The region has also experienced 83% of all AIDS deaths. Unfortunately, prior projections of the epidemic course in southern Africa underestimated the incidence of infection by half (Balter, 1998). Improved data have revealed that the prevalence rates in southern Africa are staggering: 20–26% of adults (aged 15–49 yr) are infected; in some regions 20–50% of pregnant women are infected and are likely to transmit infection to one third of their offspring. The declining mortality rate and population growth taking place in other regions cannot be extended to Sub-Saharan Africa, because of the extent of AIDS mortality (Bongaarts, 1998). AIDS has now surpassed malaria as the leading cause of death in this region (Balter, 1999). Life expectancy will fall from 64 to 47 yr by 2015. AIDS will cost, on an average, 17 yr of life expectancy in the 9 Sub-Saharan countries with a > 10% prevalence of HIV infection among adults. The child mortality rates in this region are also elevated by AIDS; rates are approximately double that expected without the HIV epidemic (UNAIDS, 1998). Within 1 yr, 2,400 Zimbabweans will succumb to AIDS per week, many in the prime of life, many leaving dependent children as orphans (up to 1 in 5 children are likely to become orphans). The United States Surgeon General, David Satcher, notes that “the progress of decades of work immunizing children, controlling diseases, and improving nutrition is being negated by HIV” (Satcher, 1999).

     In Asia, the epidemic has a mixed pattern that includes countries with slow growth in HIV prevalence, countries with some success in control efforts, and regions that appear to be experiencing explosive epidemics. Currently 7 million Asians are infected with HIV. Rapidly accelerating epidemics are possible in China, Cambodia, Vietnam, and India. Whereas urban areas were initially of greatest concern in many countries, recent information has revealed very active epidemics in specific rural areas (up to 2% of the general population), which are hosts to large proportions of the region’s population.

     Although the outlook for AIDS in Asia is bleak, there is also cause for hope. Growth of the epidemic in the Philippines is notably slow (Jacobs, 1999). Thailand has been successful in reducing the incidence of infection in sentinel population groups (such as members of the military and pregnant women) using a combination of good surveillance, effective policy response, and implementation of educational and condom promotion programs. The incidence of HIV infection among pregnant women in Thailand has dropped from a peak of 2.4% in 1995 to 1.7% in 1997 (Phoolchareon, 1998). However, ongoing political upheaval and cuts to the national HIV prevention budget may modify this pattern of success in the near future.

     In the Americas the epidemic continues to grow in specific subgroups. In the United States, as summarized earlier in this chapter, the highest incidence of infection is occurring among poor women, particularly among women of color. In Mexico the incidence of infection among men who have sex with men continues high, whereas in Brazil and the Caribbean heterosexual transmission is increasing. At surveillance sites in the Dominican Republic and Haiti the prevalence of HIV infection among pregnant women has reached 8% (UNAIDS, 1998).

     Rapid spread of infection among injection drug users in Eastern Europe and Central Asia is likely to foreshadow a large number of cases among women and increasing prevalence of perinatal transmission. The introduction of HIV into these high-risk populations has been paralleled by tremendous increases in the incidence of syphilis and other sexually transmitted diseases.

B. CONTAINING THE EPIDEMIC

Control of the HIV epidemic should be a worldwide health priority. Complex interactions of social, economic, and cultural factors have preceded AIDS with epidemics of other sexually transmitted diseases, and now hinder control of HIV itself. Global disparities in economic status have limited efforts to control sexually transmitted diseases that are much simpler to diagnose and treat than HIV. The effect of limited monetary resources is compounded by stigmatization of HIV and sexually transmitted diseases that affect willingness to seek care, social support of afflicted individuals, and health policy decision making. Traditional cultural values regarding the role of women also tend to intensify the problems. Lack of acceptance of the right of women to make decisions about childbearing and work outside the home limits options for individuals who wish to reduce the risk of infection via sexual exposures. Economic independence is a crucial factor enabling women to make some decisions themselves. The options for employment outside of sex work, for divorced or widowed women, in many societies are quite restricted. These fundamental values may directly conflict with efforts to empower women to avoid the risk of HIV and other sexually transmitted diseases (Gollub, 1999).

     To control the HIV epidemic, societies need to make deep commitments that may require an uncomfortable loss of highly valued cultural norms. Without social acceptance and encouragement, behaviorally mediated risk reduction strategies may not assume full efficacy. Vaccination is, at present, an optimal but unavailable solution. The prospects for development of an effective vaccine in the near future are not promising. Thus we have good cause to fear for the effects of HIV on women worldwide, and to increase our attention to this enormous problem as we enter the 21st century and the third decade of the HIV pandemic.

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