Factors influencing the natural history of HIV-1 infection

The natural history of HIV is defined as the untreated progression from the time of HIV transmission to death.1 The typical course of infection is characterized by three phases: acute or primary infection phase, the asymptomatic phase, and AIDS. Primary infection is often accompanied by a symptomatic acute retroviral syndrome starting 2-3 weeks after transmission and lasting an additional 2-4 weeks.1,2 The asymptomatic phase, in contrast, is long with a duration that varies widely. While there is little consensus on how to divide patients based on their duration of asymptomatic phase, multiple clinical groups have been described in the literature including rapid progressors, typical progressors, long-term nonprogressors, and elite controllers. Approximately 5% to 15% of asymptomatic subjects considered as rapid progressors experience a sharp decline in CD4+ T cell counts progressing to AIDS within 2 to 5 years. Typical progressors usually progress to AIDS within 8 to 10 years following infection.3 The 5%-15% of patients defined as long-term nonprogressors present a very slow decrease in CD4+ T cells over time maintaining normal levels for greater than ten years. Despite experiencing a slow decline in CD4+ T cell counts, most long-term nonprogressors will have low but detectable viremia and will eventually experience HIV disease progression.4 Some investigators define a small group of “elite controllers” characterized by persistent undetectable HIV viral load in the absence of antiretroviral treatment, some for over 25 years. Definitions and study techniques vary, but this group may constitute 0.1% to 1% of the HIV infected population.3,4 SURROGATE MARKERS OF HIV DISEASE PROGRESSION CD4+ T cell counts were the first surrogate marker to be used in the management of HIV. During acute HIV infection, CD4+ T cell levels fall precipitously reaching a low point around 9 days after initial infection, then re-expand by 3-4 weeks but do not reach pre-infection CD4+ T cell levels.5 This acute phase is often symptomatic but non-specific including complaints of fever, rash, malaise, sore throat, and myalgia of a week or two of duration. Higher CD4+ T cell counts early in infection are predictive of slower progression to AIDS and death.6,7 Subsequently, through the course of disease, CD4+ T cell counts decline slowly in most cases.5 During the course of disease progression, the decrease in absolute CD4+ T cell counts, in CD4 percentage of total lymphocytes, and the rates of these declines have been used in predicting progression to AIDS.8 The decrease of CD4+ T cell counts is a direct measure of immune deficiency, but do not correlate with the level of HIV replication. This can be better approximated by measuring the concentration of HIV RNA copies in plasma, known as the RNA viral load. Plasma HIV RNA viral load at baseline, HIV RNA set point, has been shown to be predictive of disease progression independent of CD4+ T cell counts.9 During acute infection, HIV RNA concentrations show an initial “burst”, followed by a decline starting two weeks after infection.5 Three to four months after infection, rapid HIV production and elimination reach a dynamic equilibrium around a steady “set-point” where HIV viral loads remain relatively constant for the duration of the asymptomatic period.5,7 While peak viral load may only weakly predict CD4+ T cell counts decline,10 higher viral load set-points serves as a strong predictor of progression to AIDS and death.6,7,9,11,12 Farther in the course of disease, generally viral load rises before CD4+ T cell counts slope worsens which occurs before clinical progression and development of AIDS.8 More severe clinical symptoms during acute HIV infection also predict a shorter time to death.7 CD4+ T cell counts and presence of HIV-related symptoms or opportunistic infections are used in US and WHO guidelines as criteria to start antiretroviral therapy.8,13 Despite their benefit in predicting progression to AIDS, neither viral load nor CD4+ T cell counts are sufficient to identify all clinical progressions. Current efforts are underway to define other markers to predict progression. FACTORS INFLUENCING NATURAL HISTORY OF HIV INFECTION The natural history of HIV disease varies considerably not only from person to person but also between geographic regions in the world. On a patient-level perspective, there are some who progress to AIDS within 2-3 years of infection and others who remain AIDS-free for more than 12-13 years. On a population-level perspective, small but important differences also exist. Geographic, societal, viral, and host factors (age, gender, exposure group, immunologic/genetic background) all may influence the natural history of HIV infection both at an individual and population level. Geography and societal factors The current HIV pandemic reaches across the globe. Across countries varying by race, access to quality health care, and rates of various co-infections, a degree of variability in the outcome of HIV patients may be expected. In a combined analysis of cohorts from the United States, Europe, and Australia before the high activity antiretroviral therapy (HAART) era, median time to AIDS excluding Kaposi's sarcoma was 10.6 years and median survival time was 11.2 years.14 Many may believe that natural progression in developing countries should be more rapid than that in developed countries. However, studies in African population demonstrated that without HAART, survival of HIV infected patients could be equivalent to patients in the developed world. Observations in a Tanzanian open cohort showed a predicted median survival of 11.5 years following seroconversion similar to that in developed countries.15 In other African studies such as in two Ugandan cohorts studied before HAART was available, the median time from seroconversion to death was 9.0 and 8.7 years, and in one study 6.2 years to a CD4+ T cell counts less than 200 cells/μl.16,17 Some studies have shown more rapid progression to AIDS and death after HIV-1 infection in Thailand than in studies done elsewhere in the developing world.18,19 Little data is available in China describing the untreated course of HIV infection. Surveys of the Chinese injection drug users (IDUs) and formal plasma donors (FPD) population noted a median infection to AIDS time of 8.5 years.20-22 New studies among broader populations are necessary to give a more representative picture of survival in China's changing epidemic. Overall, in an analysis of 8 studies from low and middle income countries, survival ranged from 7.5 years to 11.6 years median seroconversion to death.18 Given the extensive variation between study design and local conditions, there is not one figure that can be used to describe the survival of HIV patients in the developing world. Geographical variation in disease progression might reflect differences in circulating HIV-1 clades/subtypes, human genetic polymorphism frequencies, risk of exposure to opportunistic organisms, access to health care, health seeking behaviors, and nutrition. It is likely that lower population socioeconomic status accelerates the overall rate of progression to AIDS. Viral factors From broad variations in HIV-1 subtypes to mutations of individual genes, HIV-1 genetic variability at many levels may affect the course of infection. Of the two HIV types, HIV-2 infection (which is mostly seen in West Africa) progresses slower than HIV-1 infection. Patients infected with HIV-2 maintain higher CD4+ T cell counts at time of AIDS diagnosis and at death than those infected with HIV-1. CD4+ T cell counts predict clinical progression in HIV-2 patients just as they do in HIV-1 patients, but since HIV-2 progresses more slowly; CD4+ T cell counts are maintained at higher levels for a longer period of time.23 Different HIV-1 subtypes have different effects on disease progression. Kiwanuka and colleagues24 found that patients infected with HIV-1 subtype D, multiple subtypes, or inter-subtype recombinant strains had a higher risk of disease progression than subtype A. The mechanisms underlying these differences in disease progression should be further investigated but likely include both virus- and host-related factors. Nine HIV-I subtypes exist in China. Currently, B/C recombinant forms have become more predominant than subtype B strains. Of the three most common subtypes circulating in China, the percentages of B/C recombinants, subtype B, and A/E recombinants are 48.6%, 29.8% and 10% respectively.25 Studies of a few individuals infected with HIV-1 strains harboring genetic deletions or functional defects of HIV gene nef including eight transfusion recipients in Sydney infected from the same donor have shown mild HIV clinical courses with some patients having undetectable viral load after 26 years of infection without treatment.26-28 However, the conclusion and mechanism by which deletions and alternations in the HIV-1 nef gene are associated with long-term non-progression of infection, are still under dispute. Baseline viral ability to enter cells using the CXCR4 co-receptor (CXCR4 tropic or mixed CCR5 CXCR4 tropic) is associated with lower CD4+ T cell counts, higher viral load, and faster progression to AIDS.29 During the course of HIV infection, approximately one half of patients exhibit a change in tropism from CCR5 to CXCR4 with three quarters of those patients maintaining the change which often preceded a decline in immune status.30 However, among B/C recombinant forms found in China, CXCR4 tropism may be less common.31 In China, there exists a CRF07-BC recombinant strain which has mutations that influence HIV transcription resulting in a decrease in viral load and replication potential.25 Viruses that have developed resistance to various antiretroviral agents can lose some of their replication potential or fitness. It is unknown at present time if de novo infection with a resistant strain will affect the rate of disease progression in that individual. Host factors Age Age at the time of seroconversion is an important determinant of disease progression. Integrated pre-HAART data from the developed world show a clear trend in shorter progression to AIDS and death with increasing age. Excluding children infected by perinatal mother to child transmission, children under age 14 were found to have a median seroconversion to death period of greater than 13 years, those 25-34 years old of 11 years, and those older than 65 of 4.4 years.14,32 Pooled data from East African, South African, and Thai cohorts and a more recent Zambian study also show decreasing survival times with increasing age over 15 at time of infection.18-33 After initiating antiretroviral therapy older patients experience higher rates of virological response, but weaker immunological response34,35 and more AIDS events and deaths than younger patients.35 In China, cumulative cases by the end of October 2007 showed that HIV infections are concentrated in the 20 to 39 age group, who account for 70 percent of the total. AIDS cases are mainly between age 20 to 49 and this group also accounts for 69.9 percent of the total and AIDS-related deaths.36 Previous work is also insufficient to describe the natural course of disease in children, who when young, have immature immune systems which may be less effective at fighting HIV infection. Starting with acute HIV, less is known about the disease course of HIV in children. Normal CD4+ T cell counts are much higher in young children than in adults. The effect of HIV on child growth and development can be serious but is not yet sufficiently described. By the end of August 2008, there are about more than 4000 HIV-infected children identified in China and a total of 1038 are receiving antiretroviral therapy (ART) according to the national HIV database. The disease progression rate among untreated HIV-infected infants is much higher than amongst older children, adolescents, and adults. Of the 2 million people who died of AIDS during 2007, more than one-seventh were children.37 In Africa, studies suggest that one-third of newborns infected with HIV die before the age of one, over half die before reaching their second birthday, and 75% are dead before they are five years old, with subsequent lower mortality for an undetermined period.38,39 Conversely, in developed countries, preventive measures ensure that the transmission of HIV from mother to child is relatively rare, and in those cases where it does occur, a range of treatment options means that the child may survive often into adulthood.40 Recently, with HAART and effective prevent mother-to-child transmission (PMTCT) interventions, the progression to AIDS has been blunted except in sub-Saharan Africa and resource-limited settings elsewhere.41-43 Initiation of PMTCT interventions and increase in pediatric ART availability in China should reduce the number of pediatric cases and improve survival outcomes.36 Gender Globally women are disproportionately affected by HIV which becomes evident in a country once heterosexual intercourse becomes the dominant mode of transmission. As regions with concentrated epidemics like China witness an increase in HIV-positive women, greater attention is paid to natural disease progression in HIV-positive women and its influencing factors. Studies of possible differences between men and women in the course of HIV infection yield conflicting results. Early studies in the US showed women faring worse then men with a shorter AIDS to death period in one study and a higher risk of death in another. These differences were attributed to disparities in access to health care and other confounding socioeconomic factors.44 However, pooled European pre-HAART data found no difference in survival or time to AIDS between men and women after adjusting for exposure group.14 Data from studies in the developing world also fail to show a difference in survival between men and women after adjusting for age and site.18 While mortality may not differ between men and women, markers of progression and morbidity may show differences. One study found that CD4+ T cell counts in women declined faster than in men by 46 cells per year.45 A review of characteristics of HIV disease course in women noted lower viral loads in early infection, higher CD4+ T cell counts, but equivalent rates of disease progression at similar CD4+ T cell counts.46 Although Kaposi's sarcoma is more common in male than female HIV patients, HIV infected women experience a higher rate of toxoplasmosis, herpes simplex, and oral lesions than HIV infected men. HIV infected women must also face an increased risk of to infected In China, there is an of HIV infection between By the end of October 2007, of the cumulative total of people with HIV and of AIDS cases were in the course of HIV infection between men and women on the influence of gender, and race, other and socioeconomic factors such as income and should be It is that lower socioeconomic status may the rate of progression to AIDS. group Different risk exposure such as infants at or through female men who have with men injection drug users transfusion and donors (FPD) to have varying rates of HIV disease progression. extensive analysis done by the on AIDS and HIV on 13 HIV-infected individuals in Europe, and found that survival not between exposure progression to AIDS was among attributed to a higher rate of Kaposi's The rate of natural progression to AIDS was also a little higher in with This may be by the that can the of CD4+ T cells and the set point of among in showed the median survival time and median period before AIDS to be 9 years and 8 years, These are shorter than those from other countries, with differences associated with conditions, and access to and those with multiple show faster rates of progression to AIDS. A few studies on disease progression among in Africa and Thailand suggest relatively rapid disease progression in these cohorts of untreated with a median time to AIDS and to CD4+ T cell counts at 4.4 years and years A study with a cohort of in the found that the cumulative of death was within years following and within years after a CD4+ T cell counts or of an opportunistic high risk of with other exposure to opportunistic infections as as a resource-limited and access to health care may at account for the higher rates of disease progression in for progression from HIV to AIDS was greater for with time to AIDS shorter among men than among heterosexual men in Studies time to AIDS for transfusion recipients show different than those for plasma A study in of patients infected with HIV transfusion showed rapid progression to AIDS with a median period of only analysis done in that the median survival time among HIV-infected in of in China was 9 years, months after developing This difference in of disease progression between these 2 populations with HIV could be to the load of viral at time of infection. the of HIV infections from heterosexual transmission. transmission the among formal or their and their In and may also in heterosexual intercourse as populations between In China, among the various transmission the percentage of transmission is increasing transmission for of cases in but in By the end of October 2007, among the cumulative number of were infected heterosexual 1% transmission, transfusion and and mother-to-child transmission and genetic host factors Some resistance to infection or of progression may be attributed to their individual and Host genetic factors important in viral and of immune as as in to HIV infection and progression to AIDS. After infection, HIV can host production of which prevent CD4+ T cell infection. The level of is high in elite but low in HIV infected patients that high levels of may be associated with long-term HIV The same has been from studies of long-term in mutations of mainly in genes, and human and HIV cell on the CCR5 and for the mostly do not become infected with HIV. experience slower disease progression, lower viral and better virological to CCR5 mutations have been described which affect the clinical course of and can also be used as but of mutations in have not yet shown differences in disease co-receptor under has shown conflicting data as to its ability to HIV in individual are also investigated for possible of to HIV infection. The in to HIV infection by of HIV genetic HIV and it from the Although an for this may in have not been shown to affect clinical an important in the of AIDS. It can of HIV through of the transcription B and increased levels of have been demonstrated in many patients with a in the first of the gene was associated with slow progression to and have been associated with a more rapid decline of T cells during HIV infection and a faster progression to Different have an influence on HIV progression. and are risk factors for faster progression and are for and are associated with HIV long-term In China, the and high of and can be found in AIDS long-term Patients infected with HIV-1 can become with other subtypes of or other strains. While many patients with HIV show faster disease progression, HIV has also been found in HIV recombinant HIV multiple HIV infection the of the development of further recombinant strains which may have better fitness. exposure and high with other is often found in HIV B and they similar risk factors for with HIV, are often found in HIV is found in approximately 10% of HIV patients and as high as of Chinese describing the effect of on the natural history of HIV infection is In a study of patients initiating HAART, patients higher overall and AIDS-related mortality However, of describe both studies and to an effect of on progression to AIDS and the overall health of an it that HIV accelerates disease progression to disease and Approximately 10% of HIV patients are with B a of in the China may be to have a high However, available data are to exposure groups and show a rate for HIV infected and for HIV infected has not been shown to influence progression to AIDS or immunological or viral to ART in markers of have been with HAART in but they are overall to therapy infection and the and in remain present no clear that or might influence the natural history of HIV infection. antiretroviral therapy HAART has the course of HIV infection, decreasing the morbidity and mortality of infected with HIV. In developed countries, time to development of AIDS and time to death have been with the increased of In low and countries, the morbidity and mortality by opportunistic infection has one of the HIV rates in the but among the people receiving ART through health care an overall survival rate of has been After the of HAART, has also been in China with over patients having Of patients for to to or months or the viral load levels were and done in ten of in China noted that overall mortality declined from in to in after the of The of the of HAART, is not factors including HIV viral load and CD4+ T cell counts, drug and resistance are associated with different and clinical HIV natural history may be by socioeconomic gender, and characteristics of the and A better of the natural history of HIV epidemics in different and among different groups will for better to the and population in As HAART is natural history are necessary to of HIV treatment While much work has been done to describe the natural history of HIV infection in further is to better predict the progression of disease in other groups children, HIV infected women and a high of B/C recombinant and the of host genetic and with a number of HIV patients with B or or further HIV natural history in China is While exist to viral and host factors likely to influence natural only some such as tropism are available for clinical in the developed and all are from available in the developing world. techniques or may be investigated to likely natural history in settings to better for progression groups must be that from different can be more and that natural history can be for may yield treatment for different progression studies of long-term nonprogressors have about CCR5 are to studies of long-term nonprogressors have been done in the that there exist only in populations that have by countries such as China should start to identify long-term nonprogressors and start studies to for As of genetic variation of host and of that influence survival are used than to for drug A of the factors which influence the natural history of HIV disease may to the ability to predict individual HIV disease progression and identify the time to antiretroviral This for better population-level as as and treatment