I. Epidemiology And Natural History Of HIV Infection In Women

Nancy A. Hessol, MSPH,
Monica Gandhi, MD, MPH, and
Ruth M. Greenblatt, MD

Introduction  TOP

The successful introduction and spread of the human immuno-deficiency 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 infections. The existence of these new drugs changed how people perceived risks associated with sexual activity. The development of hormonal contraceptives hastened the pace of change in sexual practices, as prevention of pregnancy without barrier methods became a possibility. Lifestyles were also changing: people were moving into regions that were previously uninhabited by man and long-distance travel became easier and much more common, allowing for greater 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 26% of adult cases in 2001 (CDC, 2002). Seventy-eight percent of AIDS cases in women are in African Americans and Hispanics, as compared with 52% of cases in men.

In developing countries, the AIDS epidemic manifested quite differently, both because the signs and symptoms were harder to distinguish from competing causes of morbidity and mortality, and because the epidemic was more generalized, instead of seemingly limited to certain “high-risk” groups. Worldwide, women now represent 50% of all adults living with HIV and AIDS (Table 1-1), and this proportion had been steadily increasing over time (UNAIDS, 2002).

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 concludes with future issues regarding the HIV/AIDS epidemic.

HIV Transmission  TOP

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 within primates, HIV cannot be transmitted from casual (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 41% of reported cases as of December 2001 (CDC, 2002). This 41% is probably an underestimate given that a large proportion of the women with AIDS who report no identifiable risk (an additional 17% of AIDS cases in women) are actually also infected via sexual transmission. While receptive anal 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 anal 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%-0.10% per contact) (Lifson, 1990; Samuel, 1993; Vittinghoff, 1999; Page-Shafer, 2002) and female-to-female transmission from oral-vaginal, oral-anal, sex toy–related, and digital intercourse (Marmor, 1986; Monini, 1996; Monzon, 1987; Perry, 1989; Rich, 1993; Sabatini, 1983; Kwakwa, 2003).

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 0.3–0.4% risk per exposure, depending on the size and location of the inoculum [Tokars, 1993. Updated PHS guidelines, 2001]), and, less commonly, mucous membrane exposure (0.09% risk per exposure (Updated PHS guidelines, 2001, Hessol, 1989). Among cumulatively reported AIDS cases in U.S. women through December 2001, 39% had injection drug use as their exposure risk and 3% reported receipt of infected blood, blood products, or tissue (CDC, 2002). 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 (McFarland, 1997), and high rates of transfusion in some groups of patients. Recent data suggests that medical injections may account for a large number of previously unexplained HIV infections in the developing world (Gisselquist, et al. 2002; Gisselquist, 2002; Rosenthal, 2001).

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) overall in the absence of intervention, but vary by maternal stage of disease, use of antiretroviral therapy, duration of ruptured membranes, practice of breast-feeding, and other factors. In the United States as of December 2001, 91% of cumulative pediatric AIDS cases were attributed to perinatal transmission (CDC, 2002). 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 and the recipient, as well as 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; Gray, 2001). 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).

Table 1-2: Biologic and Host-related Factors Affecting
Sexual Transmission of HIV

Biologic Factor	Host-related Infectivity Factors
	HIV Concentration In Genital Secretions	Infetiousness (Transmission)	Susceptibility (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	?	?
Menstruation	?
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 symbol denotes that there is evidence in support of both a positive and negative association. A question mark (?) indicates an unknown or hypothesized association that is not currently supported by data.
Source: Royce, 1997. Coptright New England Journal of Medicene. Reprinted with permission.
* More recent data reveal that use of microbicides containing nonoxynol-9 are associated with a higher susceptibility to HIV infection (Roddy, 1998).

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 antiretroviral treatment reduces detection of HIV in female genital secretions (Cu Uvin, 1998) and the concentration of HIV 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). The presence of HIV in seminal cells has been documented in some individuals receiving highly active antiretroviral therapy and with undetectable levels of HIV-RNA in plasma (Zhang, 1998).

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.

Susceptibility of the Recipient

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 infections 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 a woman’s risk of acquiring HIV infection (Lazzarin, 1991) as may bleeding during sexual intercourse (Seidlin, 1993). In women, both ulcerative and nonulcerative sexually transmitted infections have been shown to be risk factors for acquiring HIV infection (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 vaginosis, may facilitate acquisition of HIV (Sewankambo, 1997; Sturm-Ramirez, 2000).

Nonbarrier contraceptive methods have also been investigated in association with risk of HIV acquisition. The most frequently studied methods of contraception have been oral contraceptives, injectable hormones, intrauterine devices, and nonoxynol-9 (Daly, 1994; Plummer, 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). Use of hormonal contraceptives does not seem to be associated with increased susceptibility to HIV infection after adjustment for behavioral factors (Kiddugavu, 2003). The use of a popular vaginal and rectal microbicide, nonoxynol-9, has been shown to have no protective efficacy against the acquisition of HIV (Roddy, 1998) and may even increase susceptibility to HIV infection due to mucosal barrier disruption, particularly with frequent use (Stephenson, 2000). The utility of other microbicidal agents for reducing the susceptibility to HIV infection is currently under active investigation.

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 antiretroviral 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. Recent data indicates that resistant virus may be transmitted less efficiently than wild-type virus (Leigh Brown, 2003), but further research on the characteristics of drug-resistant virus is underway.

Natural History and HIV Disease Progression  TOP

The natural history of HIV infection in adults has been extensively documented in the medical literature. The impact of sex on the manifestations and progression of HIV disease is still being investigated.

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. The plasma HIV-RNA level or viral load quantifies the amount of virus circulating in the bloodstream and reflects the level of HIV replication.

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 the level 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 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 1992 (CDC, 1992).

The case definition (Table 1-3) begins first with confirmation of HIV infection via either serologic testing (combination of a screening method such as enzyme immunoassay and a 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 (WHO) proposed a clinically based staging system that is more broadly applicable than the CDC system (WHO, 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; Jacobson, 2003; Badri, 2003).

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 WHO 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 WHO 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 WHO clinical stage with CD4 cell count and clinical outcome (Morgan, 1997; 1998; Schechter, 1995). When compared with the CDC staging, the WHO 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 WHO 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 than percentage of body weight lost over two measurements taken in 1 year at predicting mortality. 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 WHO 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 is actively being investigated (Rosenberg, 2000) (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. In the case of a high viral load set point (i.e., values ranging up from 40000 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 sex (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 resulted 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 over time. 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, intracellular 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 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). Almost half of seroconverters will die (due to any cause) after 10 years of infection if the disease is left untreated (Vella, 1992). 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 have 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 HIV-infected 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). These individuals are often called long-term nonprogressors. 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 HIV-uninfected donors (Cao, 1995).

Sex Effects

Concerns about sex-based differences in the course of HIV infection were expressed early in the epidemic. Women appeared to have more rapid progression of illness than men and to present with a different constellation of opportunistic conditions than men. However, current data suggests that the incidence and distribution of HIV-related illnesses are similar by sex, with the exception of Kaposi’s sarcoma, which is uncommon in women, and gynecologic manifestations of HIV. When sophisticated statistical methods were applied that controlled for the tendency of women to receive less care and to present with more advanced disease, sex-based differences in HIV disease course appeared to be eliminated. 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 sex-based 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; Sterling, 2001). A recent epidemiologic review of 13 studies, 4 of which were longitudinal, confirmed these findings, which were unchanged after adjustment for potential confounding variables, such as age, race, mode of transmission, and antiretroviral treatment (Gandhi, 2002). Intuitively, lower levels of circulating HIV RNA, which suggest lower steady-state levels of viremia, should be associated with better outcome. However, the lower HIV RNA level seen in women does not appear to provide benefit in terms of disease progression or survival. Viral load differences tend to dissipate several years after seroconversion and rates of progression to AIDS are similar by sex (Sterling, 1999; Sterling, 2001) when examined in men and women followed from seroconversion. [Studies have also suggested that CD4 cell counts are higher in women at onset of AIDS (Prins, 1999) but that CD4 cell depletion may occur more rapidly in women as compared to men (Anastos, 2000).]

Determination of the effect of sex 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, HIV-infected women and men differ by more than just their biologic sex. Women tend to have lower income, be un- or underinsured for health care, 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 (Feldman, 1999), among women compared with men (Melnick, 1994; Weisser, 1998).Factors that influence disease progression are summarized in Table 1-6.