Natural history of HIV-1 infection

Natural History of HIV-1 Infection GIOTA TOULOUMI, PhD ANGELOS HATZAKIS, PhD

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he human immunodeficiency virus type 1 (HIV-1) infection is characterized by a long and often prolonged asymptomatic period after initial infection. A number of early epidemiological studies, and particularly prospective incident cohort studies (ie, cohort studies with known seroconversion dates), provided estimates of the AIDS incubation period in different population groups and investigated several host and virus factors for their potential prognostic value. The development of new techniques for sensitive and accurate quantification of HIV-RNA in plasma and/or serum has revolutionized studies of the natural history of the HIV-1 infection. It is now realized that the viral pathogenesis is a highly dynamic process reflecting the various properties of HIV-1 and the host’s immune response to the virus. The increased clinical experience and the introduction of primary prophylactic therapy have altered the spectrum of AIDS-related conditions and the natural history of the infection. Antiretroviral treatment with reverse transcriptase inhibitors (RTI) has shown to have a sizable but transient beneficial effect. The impressive recent advances in treatment with the availability of protease inhibitors (PI) may radically change the natural history of HIV-1 infection. Initial results from clinical trials suggest that highly active antiretroviral therapy (HAART), which combines RTI and PI, results in viral-load reduction and possibly long-lasting immune recovery. For adults in developed countries, in the absence of antiviral therapy, the median time from initial infection to the development of AIDS is about 10 to 11 years; however, there are individuals who progress to AIDS within 5 years of infection and others who remain AIDS-free for more than 15 years. Factors influencing the HIV-1 disease progression have received important consideration. In this review, the natural history of the HIV-1 infection in different populations and the effect of several host and/or virus factors on it will be discussed. From the Department of Hygiene and Epidemiology, University of Athens, Athens, Greece. Address correspondence to Angelos Hatzakis, PhD, Department of Hygiene and Epidemiology, University of Athens, M. Asias 75, Athens 11527, Greece. © 2000 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

The Course of HIV-1 Infection Infection with HIV-1 initiates a process that leads to progressive destruction of CD4 T lymphocytes, the target cell preference for HIV-1 infection.1 The course of the HIV-1 infection varies widely from person to person. A typical pattern of HIV-1 infection in vivo is characterized by three phases (Fig 1): the acute or primary infection, the asymptomatic, and the symptomatic phase. Primary infection, which generally lasts for 2 to 8 weeks, is typically associated with high levels of virus. Concentrations of plasma HIV-1 RNA can exceed 107 copies/mL.2,3 A proportion of infected individuals present clinical symptoms, including fever, lymphadenopathy, pharyngitis, and cough during primary infection.4 – 6 With the emergence of antiretroviral immune responses, and in particular of specific cytotoxic T lymphocyte response, levels of plasma HIV-RNA decline precipitously.7–9 After about 6 months of infection, plasma HIV-RNA stabilizes around a so-called set point, and it remains relatively constant during the asymptomatic phase.10 –13 There are, however, large differences in the set points of plasma HIV-RNA among subjects.14 –16 Recent studies have revealed that during the clinically latent phase of disease, there is a very dynamic process of virus production and clearance.17–21 It is estimated that approximately 30% to 50% of the total viral population in plasma is replenished daily. Concurrent with the onset of clinical symptoms, levels of HIV-1 viremia increase and remain raised throughout the terminal phase. During primary infection, the number of CD4 T lymphocytes decreases dramatically but returns to a near normal level within 3 to 4 months after infection. The asymptomatic phase is characterized by a slow, gradual depletion of CD4 T lymphocytes, but the rate of decline varies substantially among individuals.22–25 Instead, the number of CD8 T lymphocytes rises during primary infection, then returns to a level somewhat above the normal and stays elevated till the final symptomatic phase. The mechanism by which the human immune system regulates the total number of T lymphocytes is poorly understood. It has been proposed26 that the aggregate number of CD3 T lymphocytes remains approximately stable during the early and intermediate stage of HIV-1 infection. Thus, the human immune system 0738-081X/00/$–see front matter PII S0738-081X(99)00134-0

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clear, cofactors of HIV-1 disease may be considered as risk modifiers that are causally associated with the disease.36,37 Cofactors have been distinguished between fixed, such as genetic factors or age, which are already present at the time of infection, and variable, such as infection with other viruses or general lifestyle factors, that could take place after HIV-1 infection has already occurred and may change over time.36 –38 In the context of HIV disease, a marker is described as a consequence of infection that varies over time but does not necessarily predict disease progression.36,37

Host Factors HIV-1 SEROCONVERSION Age at HIV-1 seroconversion (SC) is one of the cofactors consistently associated with disease progression. Children under 15 years of age at SC have been shown to have a different natural history of HIV-1 infection from adults,39 which can be partly explained by the different (perinatal) mode of HIV-1 transmission. Among adults, greater age at SC is associated with faster progression rate to AIDS and/or death in homosexual men,40 – 42 blood-transfusion recipients,43,44 intravenous drug users (IDU),45 and especially in hemophiliacs46 –50 where the age-range is the widest. A few studies have failed to show an age effect,51–53 but this has been mainly attributed to the small number of subjects and/or to the narrow age intervals. Several possible mechanisms through which the age effect may operate have been proposed. It has been suggested that the effect of age may be mediated through a more rapid decline in immune system,54,55 an early decline in the CD4 cell count,56 a reduction in the capacity to regenerate CD4 cells at older ages,21 or by different immune responses after chemotherapy at different ages.57 AGE AT

Figure 1. Typical pattern of HIV-1 infection in vivo. (From Coffin JM. HIV viral dynamics. AIDS 1996;10 (Suppl 3): S75– 84).

strives to maintain homeostasis of specific T-cell numbers without discrimination between specific T-cell subsets (“blind homeostasis”). At about 18 months prior to the development of AIDS, blind homeostasis breaks down, resulting in a loss of total T cells and eventually in immune collapse. In some cases, the number of T lymphocytes drops precipitously within a few months, probably mirroring a return to high-level virus production.27,28 The reasons for homeostasis failure are unknown, but they could include exhaustion of the proliferative capacity of lymphocytes and/or progressive deterioration of the architecture of the lymphoid organs.1 During the acute phase the virus population is homogenous, but it becomes heterogeneous during the asymptomatic period with the emergence of virus variants in the face of the immune response. Virus population becomes again homogenous during the symptomatic period, when anti-HIV immune response is absent or low.29,30 Most of the AIDS-defining symptoms occur when CD4 T lymphocytes are below 200 cells/␮L; however, patients with AIDS do not form a homogenous group. Different AIDS-defining illnesses occur at different levels of CD4 T lymphocytes and have different prognosis. For example, Pneumocystis carinii pneumonia (PCP), Kaposi’s sarcoma, or tuberculosis as first AIDS-defining diagnoses are considered mild, whereas other AIDSassociated diagnoses such as non-Hodgkin’s lymphoma are considered more severe.31–35

Cofactors in HIV-1 Infection During the past two decades a considerable number of studies have been conducted on potential cofactors and markers of HIV-1 disease progression. Although the distinction between cofactors and markers is not always

Differences in the rate of HIV-1 disease progression by ethnicity, exposure group, and gender are in general small40,58 – 64 and can be explained by differences in related factors such as age at SC, risk behavior, access to care and frequency of different AIDS-defining conditions, which are themselves associated with progression. The frequencies of AIDS-defining conditions differ substantially by exposure group.65 For example, cytomegalovirus (CMV) and Kaposi’s sarcoma (KS) are markedly increased among homosexuals, whereas HIV-encephalopathy, mental disorders, and cachexia are more often observed in IDUs. Differences in infectious-agent exposure (KS, CMV, herpes simplex for homosexuals, hepatitis for IDUs) or in general health (poor in IDUs) and lack of medical care may explain the observed differences among risk groups. The increasing number of women worldwide infected with HIV-1 and the higher efficacy of male-tofemale transmission of HIV-1 has greatly enhanced the interest on HIV-1 disease progression among women. ETHNICITY, EXPOSURE GROUP, AND GENDER

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Women experienced a higher incidence of PCP than did men in 1989, but that was almost certainly related to the delayed entry of women into clinical trials.60 Invasive cervical cancer, one of the new AIDS-defining diseases associated with a number of gynecologic disorders, is apparently more frequent among HIV-positive women; however, there are still few data to explain the effect of this condition on the natural history of HIV-1 in women. Other malignacies, such as KS and lymphoma, are less frequent among women than men.62,63 Opportunistic infection (OI) occurring at higher rates in women than in men are bacterial pneumonia, esophageal candidiasis, and herpes simplex ulcerations. Pregnancy and hormonal changes have been proposed as factors that could influence the progression of HIV-1 infection.63 Recent results66 indicated that after controlling for CD4 cell count before conception, pregnancy does not significantly accelerate disease progression. Researchers67 have found that median viral-load levels were lower in women than in men, and this difference remained even after adjustment for CD4 cell count. Time of progression to AIDS was not significantly different statistically among women and men, but women with the same viral load to men had significantly higher risk of developing AIDS. The investigators suggest that, although the biological mechanism remains unclear, current recommendations of HIV-1 viral-load thresholds for initiation of antiretroviral therapy should be revised toward lower values for women. This issue definitely needs further investigation. Temporal changes in the definition of AIDS, increased clinical experience, and the impact of prophylactic and antiviral therapy make the interpretation of changes in the AIDS incubation period over time difficult. Investigators68 reported shorter median time to AIDS and death than previously reported in seroconverters for the Multicenter AIDS Cohort Study (MACS); this was due to improved ascertainment of AIDS cases and death among patients in the cohort. In an Italian incident cohort study69 it was found that subjects infected after 1989 had poorer disease outcome (ie, steeper CD4 decline and faster progression to AIDS), even after controlling for other factors related to disease progression. Shorter AIDS incubation periods in cohorts of recent seroconverters could suggest increasing virulence of the infectious agent. Results from large cohort studies of homosexual men and IDUs have shown that changes of immunologic markers at HIV-1 infection do not show calendar trends suggestive of increased virulence.13,59,70 In the era of antiretroviral combination therapy, with the virus resistant to one or more antiretroviral drugs, the effect of primary infection on the natural history of HIV-1 infection has not yet been determined. CHANGES IN INCUBATION PERIOD OVER TIME

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Natural history studies have failed to show a statistical association between alcohol and other psychoactive drugs and overall AIDS progression rates.30,37 It has been shown that lower socioeconomic status is associated with high-risk behavior.71 Socioeconomic status has also been associated with HIV-1 disease progression, but this association has been, at least in part, attributed to differential access to health care.37 There is some evidence, however, that lower socioeconomic status may lead to faster course of HIV-disease, independent of age at SC, CD4 cell count, and clinical treatment.37,72,73 Vitamin A deficiency may also increase the probability of vertical transmission and risk of progression to AIDS.74,75 There are no consistent results about the effects of psychological stressors on the course of HIV-1 infection.30,37 LIFESTYLE FACTORS

It has been suggested that immune activation from long-term exposure to several antigens or infectious agents may increase susceptibility to HIV-1 infection and enhance progression to AIDS.30 Convincing evidence shows that STDs, particularly those leading to genital ulcers, act as important cofactors of HIV-1 transmission, but their role as cofactors of HIV-1 disease progression is less clear. In a study where female sex workers were compared with mothers participating in studies of vertical transmission, the sex workers progressed to AIDS faster.76 The observed difference could be partly explained by the exposure of sex workers to STDs. Mycoplasma femetans has been isolated from HIV-1 infected subjects and was believed to be associated with an increased risk of disease progression.77 Most evidence, however, suggests that mycoplasma does not play an important role in HIV-1 pathogenesis.30,37 Herpesviruses could also be important in the HIV pathogenesis. Some studies have suggested that HIV-1 acts as a cofactor in herpesvirus infections by enhancing or suppressing their replications,78 – 80 probably through cytokine production.30 One study suggested that prior infection (prevalent) with CMV was a significant prognostic factor of progression to AIDS or death in hemophiliacs.81 In contrast, other studies in hemophiliacs failed to show such an association.50,82,83 Differences in selection methods or in the baseline prevalence rates of other viruses could explain the contradicting results; however, incident CMV has been associated with faster HIV-1 disease progression.83 Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) does not seem to affect the course of HIV infection, but HIV can influence the natural history of chronic HBV or HCV infection.84 – 86 HIV infection has been shown to accelerate progression of HCV infection.84 OTHER VIRUSES

Host factors may influence the course of HIV-1 infection by inducing a more effective immune response. The role of major histocompatibility GENETIC COFACTORS

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complex (MHC), human lymphocyte antigen (HLA) for humans, and Class I and II phenotypes has been investigated in a number of studies.87–93 Specific combinations of HLA genes have been associated with either relatively rapid (eg, A1, A9, A23, A26, B8, DR3, DR2, DR5) or delayed (eg, A9, A25, A26, A32, B5, B14, B18, B27, BW4, DR6, DR7, DR13) progression to AIDS; however, there is no conclusive evidence of a link with a particular HLA type. Inheritance of specific genes, other than HLA genes, might also affect the rate of HIV-1 disease progression. The CCR5 gene is a principal cellular chemokine (ie, RANTES, MIP-1a and MIP-1␤) receptor that serves as an efficient co-receptor for HIV-1.94 –96 This receptor is utilized by HIV to enter into macrophages, whereas another chemokine receptor (CXCR4) is utilized by HIV to enter into a broad spectrum of T cells.97,98 Two other genes, CCR2, which forms an alternative portal to macrophages for HIV-1, and SDF-1, a gene that codes not for a receptor but for its chief endogenous ligand, have been discovered. For the CXCR4 gene, no allele differences have been found among humans; however, CCR5 and CCR2 mutant alleles have been described (CCR5⌬32 and CCR2-64I, respectively). Homozygotes for CCR5-⌬32 mutant allele are resistant to HIV-1 infection,99 –101 but CCR2-64I mutation does not seem to have an effect on the incidence of HIV-infection.98 Several reports have suggested that both CCR5-⌬32 and CCR264I have a protective effect on HIV-1 disease progression, but the two mutations have never been found in the same chromosome haplotypes.102–105 Like CCR2-64I, the mutation in SDF-1 showed no effect on a person’s risk of HIV-1 infection; however, similar to the other two gene mutations, it has been shown to be beneficial in delaying progression to AIDS.106 Moreover, the effect seems to be additive; that is, persons with protective genotypes of both SDF-1 and CCR5 or CCR2 gene have a lower risk of disease progression than do those with only one kind of genetic protection.98 The frequency of individuals who have one or more protective genotypes is substantial: 39.1% of Caucasians and 31% of African Americans.107 Recently, it was reported that a promoter variant of CCR5, namely CCR5P1, is associated with a faster progression to AIDS.107 The CCR5P1 is the first allelic variant to accelerate AIDS progression. Its frequency is 12.7% in Caucasians and 6.7% in African Americans.107 Both the cumulative and interactive influence of these genes illustrate the multigenetic nature of host factors on the HIV-1 disease progression.

Viral Factors A potentially important prognostic marker is the viral phenotype. The HIV-1 variants that induce syncytium (SI) formation (fusion of cells into a single multinucleate cell) have been more closely associated with a rapid progression to disease than the non-syncytium-induc-

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ing (NSI) variants108,109; however, a shift in the viral phenotype from NSI to SI phenotype is not necessarily associated with progression to AIDS.110,111 The NSI isolates can be detected throughout the course of HIV-1 infection, but SI isolates usually emerge only during the progression of HIV-1 infection and precede the onset of AIDS in about 50% of progressors.112,113 Some studies suggest that, early in HIV-1 infection, NSI progressors can be distinguished from nonprogressors on the basis of serum HIV-RNA load and SI progressors on the basis of CD4 cell decline.11,113 Some studies indicated that deletions in the nef gene of the virus may be associated with slow progression to disease114,115; however, deletion in the nef gene does not account for nonprogression in most subjects.30,116

Markers Identification of markers of a disease progression that can be utilized as potential surrogates for clinical outcomes is very important, especially for diseases with long incubation period, for at least the following reasons: (i) to gain insights into the natural history and pathogenesis of the disease, (ii) to be used as surrogate endpoints in clinical trials, and (iii) to identify patients at high risk for whom it may be appropriate to intensify treatment. The ideal marker would be able to predict disease progression, be responsive to therapy, and explain the variance in clinical outcome due to therapy.117 In the context of HIV-1 infection, several immunological and virological markers have been examined.

Immunological Markers Among several immunological markers, the absolute number of CD4 cell count remains the most powerful predictor of HIV-1 disease progression.22,23,27,30,36,55,118 –120 A low CD4 cell count is strongly associated with increased risk of development of opportunistic infections (OIs) and disease progression. A CD4 cell count below a certain threshold is used as criteria for the initiation of antiretroviral or prophylactic therapy and often to set entry criteria for clinical trials. Since January 1, 1993, a CD4 cell count below 200 cells/␮L has become part of the AIDS definition in the United States. Despite its adoption as a key disease marker, the CD4 cell count shows substantial laboratory and physiologic variation. Also, the number of CD4 cell count can be affected by other illnesses and/or pharmacological agents.121 Moreover, progression to AIDS has been reported in individuals with a relatively high number of CD4 cells, whereas some individuals have remained AIDS-free for extensive periods despite their very low CD4 cell count.30,36 These results indicate that this marker alone is not a reliable predictor of disease. Although the CD4 cell count is a proxy measure for HIV-related immunosuppression, it is not necessarily

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an indicator of overall immune function. Marked defects in CD4 cell count function often precede substantial declines in the number of CD4 cells. Memory T cells, which represent that part of the T-cell repertoire activated by exposure to antigen in the recent past, are preferential targets for HIV infection. The memory pool includes mainly CD4 cells with specificity to several agents associated with OIs. The gradual depletion of memory CD4 cell count predisposes the host to OIs; however, memory CD4 cells seem to have a slower decline than do naive CD4 cells, probably due to their greater proliferation rate, which outweighs their larger susceptibility to HIV-1 infection.1,30,122 The delineation of CD4 subsets may also be a useful marker of disease progression. Several studies suggest that prior to HIV infection and during the early stages of HIV-1 infection, the dominant subset is TH1, which produces cytokines (such as IL-2 and IFN) that enhance cellular immunity. As the infection progresses it is replaced by the TH2 subset, which produces cytokines (such as IL-4 and IL-10) that boost antibody production.1,30,36,123,124 It has been suggested that increased production of TH2 cytokines reduce the production of TH1 cytokines and could directly decrease the antiviral responses of CD8 cells.30 The shift from TH1 to TH2 subsets has been associated with disease progression.30,36,125,126 Anti-HIV CD8-cell activity (both cytotoxic and noncytotoxic) is decreased in individuals progressing to disease, but CD8-cell noncytotoxic activity remains strong in long-term nonprogressors.30,127–130 This CD8⫹ cell activity depends on a strong type 1 cytokine production.131 Cytotoxic T-cell activity has also been associated with nonprogression.36 Elevated levels of neopterin and ␤2-microglobulin have been associated with increased risk of disease progression.36,118,132,133 Neopterin and ␤2-microglobulin levels are highly correlated with each other, and they are both nonspecific indicators of lymphoid cell activation. Elevated levels of neopterin or ␤2-microglobulin have been associated with Kaposis’s sarcoma in homosexuals36,134; however, the independent prognostic value of these two markers is not clear. It has been suggested that levels of ␤2-microglobulin may be useful only as a late marker of disease progression.135 HIVspecific antibodies were among the earliest identified markers of HIV-1 disease progression.136 Levels of IgA have also been associated with disease progression, but the independent prognostic effect of IgA compared to other markers seems to be weak.36

Virological Markers The p24 HIV core antigen is one of the earliest virological markers; p24 antigen disappears for a period of time. Persistent HIV antigenemia is associated with faster progression to AIDS36,136; however, inconsistent

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results about the predictive value of p24 antigen have been reported among different risk groups.36 Development of relatively new techniques for quantification of HIV-RNA plasma levels enabled the monitoring of virus replication. Concentrations of plasma HIV-RNA during the steady-state period vary substantially among subjects, ranging from less than 50 copies/mL to more than 106 copies/mL. Recent studies show that the HIV-RNA level during early chronic infection (steady-state phase) is a strong predictor of disease progression.10,14 –16 Furthermore, higher HIV-RNA levels are associated with lower number of CD4 cells,2,11,12,15 whereas subjects with higher levels of HIV-RNA early in the course of infection are likely to reach a critically low CD4 cell count sooner than subjects with lower levels.25,137 These results are consistent with HIV-RNA being an early and strong prognostic factor of disease progression, and, in conjunction with the findings that persons with acute symtomatic primary infection tend to progress to AIDS more rapidly than people with low-grade or asymptomatic primary infection,138,139 they indicate that fundamental aspects of the host–virus relation are established early in the course of the infection. Results from several clinical trials show that druginduced changes in HIV-RNA levels are predictive of disease progression and that these changes may be more important than baseline levels themselves. Although levels of HIV-RNA during early chronic infection consist of an early and powerful predictor of disease progression, it has been shown that with ongoing infection, the predictive value of CD4 cell count and T-cell function increases, whereas the predictive value of high HIV-RNA level decreases,140 –142 indicating that in later stages the degree of immune deficiency is most predictive of disease progression.

Patterns of HIV-1 Disease Progression Adults In HIV-infected adults, three clinical groups of individuals have been described: rapid progressors, typical progressors, and long-term nonprogressors (LTNPs).30,143 Rapid progressors are characterized by the sharp decline in the CD4 cell count soon after infection and by their high levels of HIV-RNA that do not decrease substantially after acute primary infection. They progress to AIDS usually within 2 to 5 years after seroconversion. In typical progressors, a gradual decline in the number of CD4 cells and in T-cell function is observed over time. They usually progress to AIDS within 8 to 10 years following infection. The third clinical group (LTNPs) consist of individuals who have remained healthy and with normal CD4 cell count for more than 10 years. The LTNPs are characterized by low virus load, type 1 cytokine production, and strong

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cellular CD8-cell antiviral response; however, whether LTNPs are a discrete group who will never progress or whether they simply represent very slow progressors has been debated for some time.128,144 Although several viral and host factors have been associated with nonprogression, their relative contribution in determining LTNPs remains unclear.59,60 Most of the studies do not support the hypothesis that LTNPs are a discrete group of patients. In fact, in most studies it has been shown that a third to a half of LTNPs had progressed within 3 to 4 years of being defined as LTNPs. The definition of an LTNP varies substantially among different studies and this may explain the different findings.

Children The evolution of HIV-1 infection acquired by vertical transmission is more rapid in children than in adults.145,146 The median survival in HIV-1-infected infants ranges from 75 to 90 months, and only 70% of children reach the age of 6 years. About 15% to 20% of infected infants develop severe immunosuppression and experience opportunistic infections (OIs) and encephalopathy in the first year of life and die within the first 3 years. The remaining 80% to 85% experience a slower disease progression and live for several years. The reasons for rapid progression are not well understood; however, several maternal, infant, and viral factors may influence the natural history of HIV-1 infection in children. The rapid-progressor group consists mainly of infants with intrauterine transmission, whereas the slower-progressor group consists mainly of infants infected closer to birth. Both the development of OIs or encephalopathy147 and delayed growth and weight gain148 are associated with fast progression, whereas lymphocytic interstitial pneumonitis, hepatosplenomegaly, and parotitis are associated with slower disease progression.145,149,150 The severity of maternal disease, the infant’s immune response, and viral load are also associated with disease progression. Although viral load may be undetectable at birth, it rapidly reaches high levels, higher than in adults, and it may take several years to be stabilized at lower levels (steady-state phase). In children, HIV-1 infection is also characterized by the gradual depletion of CD4 cell counts; however, normal ranges of CD4 cells are higher in children than in adults, and they gradually decline over the first few years of life. Consequently, children may develop OIs at higher CD4 levels than adults.145,151 Furthermore, immunological classification of children needs to be agespecific. It has been reported that many HIV-1 infected children who had experienced early onset of lymphadenopathy, rash, or wasting syndrome died before meeting an AIDS criteria.152 These results suggest that manifestations of HIV may differ in children, and fur-

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ther modification of the AIDS definition may be required to reflect more accurately the disease burden in children.

Conclusions Although the complex interactions between host and virus involved in the HIV-1 infection have not yet been completely clarified, our understanding of both the natural history and the pathogenesis of HIV-1 infection has considerably advanced since the first reports of AIDS. The availability of protease inhibitors and the wide application of HAART may radically change the incubation period of HIV-1 infection. Initial results of clinical trials suggest that HAART could induce long-lasting immune recovery and viral-load reduction. Although these initial results are promising, several major questions remain to be answered. These include the optimal time of therapy initiation; emergence (and probably transmission) of drug-resistance virus’s mutations; long-term effects of therapy; ability to recover the immune function in patients with advanced disease; and approaches to maintain strong immune responses to HIV-1. Well-organized clinical trials could answer several of these questions, but the large number of potentially useful combinations of all available antiretroviral drugs makes their evaluation impractical. Conversely, as the interpretation of observational cohort studies becomes more difficult, such studies can provide valuable insights into the natural history of HIV-1 infection and can successfully complement clinical trials and laboratory studies in the new era of combination antiretroviral therapy.

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