Context: Survival in Human Immunodeficiency Virus infection (HIV) /Acquired Immunodeficiency Syndrome (AIDS) is on the rise. AIDS manifest due to a complex failure of adaptation between the HIV and the host. Coexistence of Simian Immunodeficiency Virus (SIV) in primates has been suggested as survival replacement by long-term nonprogressors (LTNP) following a retroviral epidemic in the remote past. Studies have postulated a constant evolutionary pressure between the HIV virus and the host with a possibility of an analogy with the SIV model.
Aims: To evaluate increasing survival period if any, post HIV infection, in patients without anti retroviral treatment (ART).
Settings and Design: Longitudinal cross-sectional study on hospital follow-up patients of HIV infection.
Methods and Material: 491 consecutive cases of HIV infection reporting to our referral centre during a period of 24 months were evaluated for history of last known risk behaviour or other modes of transmission,CD 4 counts and other parameters as per a defined protocol.
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Statistical analysis used: The main results are described in absolute values and percentages.
Results: 64 of the 491 cases of HIV patients (13%) were found to have HIV infection for a presumed duration of 8 to 26 years (mean of 14.75 years at diagnosis). About 1.4-2.8% patients in our case series were long-term nonprogressors (as per different definitions) and 3% patients were long-term survivors. 57 patients out of 64 as above (11.6% of all cases) did not satisfy the criteria for LTNPs but had survived long enough (mean 16.2 years and range 8-26 years) without ART.
Conclusions: The average time from primary HIV infection to the development of AIDS in untreated individuals in the developed world is about 10 years and much less in developing world as per conventional teaching. The findings of our study perhaps reflect a shift in the trend of mortality pattern in the developing world, with a longer survival without treatment.
Key-words: Long-term nonprogressors, long term survivors, HIV
AIDS manifest due to a complex failure of adaptation between the HIV and the host. Studies have postulated a constant evolutionary pressure between the HIV virus and the host resulting in changes in the virus and the host response. This has already starting showing as a shift in the trend of mortality with longer survival.
The term progression is used to express the course from HIV infection to AIDS to death. In treatment-naive patients, or in patients in whom therapy resulted in poorly controlled virus replication , after a variable period, usually calculated in years, the CD4+ T cell count falls below a critical level (<200/Âµl) and the patient becomes highly vulnerable to opportunistic disease. This process is inexorable, though there may be a long duration between the onset of HIV infection and the first AIDS-defining disease. There exist several multifarious anomalies in the natural history and pathophysiology of HIV Infection.
The full continuum of symptoms related to AIDS, or laboratory evidence of immunodeficiency, develops in a bulk of infected persons in less than 10 years of seroconversion (1,2). Nonetheless, about 5 percent of HIV positive persons remain clinically healthy and immunologically normal for more than a decade (1). This subset of patients, infected with HIV for 10 years and longer, having CD4+ T cell counts in normal range, and remaining stable over years without receiving ART, is referred to as LTNPs (1).
Some authors have used a cut-off criteria of seven or eight years instead of ten years for defining LTNP (2,3). There are no known demographic or behavioral variables which help to distinguish LTNPs, and few studies have been done to evaluate geographically and ethnically dissimilar groups. If individuals remain alive for 20 years after initial infection, they are considered to be long term survivors (LTS) (3). In most such patients, the disease is advanced, with significant immunodeficiency and episodes of opportunistic diseases. The CD4+ T cell counts in some of these patients are around 200/Âµl or below but have remained stable at that level for years.
The global proliferation of human immunodeficiency virus (HIV) over the past four decades is one of the most cataclysmic examples of the emergence, transmission, and propagation of a microbial genome (4). Many viral and host factors with their complex interactions, influence the course of the infection and the ability of ART to reduce the viremia and establishment of viral reservoir (5).
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Striking shifts in mortality within human populations worldwide are already being seen due to variable host susceptibility to HIV infection and its virulence. There is mounting data that supports the theory that the evolutionary pressure resulting from the differences in virulence and disease progression of HIV in human hosts is causing genetic changes in the virus itself (6).
With this background, we proceeded to evaluate the increase in survival period if any, in treatment naive HIV patients at our centre.
Subjects and Methods:
We evaluated 491 consecutive HIV positive patients who reported to our referral centre over a period of 24 months. These patients were detected to be HIV positive either in the past or during the period of the study. Complete past medical records of all patients were either in their possession or in our data bank, our centre being the regional referral centre for HIV/AIDS.
All HIV positive patients who reported at our centre were included in the study.
All the patients were evaluated for current age, month/year of last known high risk sexual behaviour, intravenous drug use (IDU) or any other potential route for acquiring HIV infection (like blood transfusion, sharing of therapeutic injection needles in any remote health care locality/by quacks, sharing of razors, etc), number of sexual partners: current and past, mode of detection of HIV (voluntary screening or high risk screening), and year of detection of HIV infection. All past medical records were perused. All patients were subjected to a detailed history and complete clinical examination for signs of HIV disease or opportunistic infections. All patients underwent analysis for CD4+ T cell count at first detection, six monthly for first one and half years and yearly thereafter. A basic Hemogram, urine analysis, Liver function tests and serum creatinine was carried out. Screening for syphilis, hepatitis B and C was also done. Yearly Chest X ray and ultrasound of the abdomen were done. Computerised tomography (CT) scan of abdomen, head and chest was carried out in relevant cases. Baseline and thereafter two yearly Mantoux test was done. Baseline and thereafter two yearly Toxoplasma, Herpes Simplex virus 1 &2 and Cytomegalovirus antibody titres of IgG and IgM were also done. Serial weight records were also maintained. Any other relevant tests required for treatment of any specific cases were also undertaken.
The last known instance of high risk behaviour or any other known method of transmission of HIV infection, historically, or date of seroconversion was taken as the time of onset of HIV infection, as done in other studies (1). All patients with a minimum time of eight years from presumed time of onset of infection were then screened out as potential LTNPs. Finally, patients who exhibited no signs of opportunistic infection or AIDS-defining criteria, and had CD4+ T Cell count of 600 cells/Âµl or more at eight years from presumed onset of HIV infection, were selected and followed up.
All cases were male patients. The duration of infection in 18 patients (out of a total of 491 cases) was calculated from the date of seroconversion (four were healthcare workers previously known to be seronegative and seroconverted after needle stick injuries; five patients who were seronegative prior to blood transfusion , had seroconverted 3-4 months after the procedure in the late 80s and early 90s after apparently inadequately tested blood transfusions; nine patients had indulged in high risk sexual behaviour of short duration and got themselves voluntarily screened later). The duration of infection in the balance of the cases was documented historically as defined above. 64 of the 491 cases of HIV infection (13%), on follow up at our centre, were found to have the infection for a presumed duration of 8 to 26 years, with a mean duration 14.75 years at diagnosis (Figure 1). 7-14 of these 64 cases (1.4-2.8% of 491) patients satisfied the criteria of LNTPs as per different definitions (10 versus 08 years as cut off . 15 patients (3% of 491 cases) in our case series satisfied the criteria of LTS. Both LTNP and LTS groups had overlaps. The mean CD4+ T cell count of these 64 patients was 339cells/Âµl. Thus 13% of patients had survived from 8 to 26 years after infection without need for ART and were maintaining reasonable CD4+ counts.
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The patient with the maximum duration of illness i.e. 26 years (onset in 1984-85 with last exposure to CSWs) was detected in Jul 2003 with a CD4+ count of 580 cells/Âµl and thereafter on follow up for 7 years. He was put on ART in 2004 and is otherwise asymptomatic till date. Another patient with a duration of disease of eight years was detected in Dec 2007 with a CD4+ T cell count of 608 cells/Âµl. The patient with the longest period of follow up since detection (in 1996) had a presumed duration of infection of 15 years (onset in 1995 with multiple exposures to CSWs). He had a CD4+ T cell count of 639 cells/Âµl at onset and still maintaining counts above 500 cells/Âµl without ART. Another patient with duration of infection of 25 years (history of blood transfusion in 1985 and no other high risk behaviour or other modes of infection) is in observation since Dec 05 after screening during a blood donation camp, and is maintaining CD4+ counts in range of 793-811 cells/Âµl. The average duration of follow-up of all 64 cases since the time of detection till the completion of study (Oct 2010) was 4.4 years (range 1-14 years).
The ages of all patients ranged from 27 years to 51 years with a mean of 39.51 years. There were few surprises also. 57 patients (11.6% of all cases) did not satisfy the criteria for LNTPs with mean CD4+ T cell count of 334 cells/Âµl (missing the definition of LTNP by a few hundreds for the CD4+ T cell counts) but had survived long enough (mean 16.2 years and range 8-26 years) without ART (Figure 2). 31 cases out of 64 cases as above had a CD4+ T cell count below 350 cells/Âµl at diagnosis (threshold for starting ART at our centre ) or few months thereafter with an average time duration of HIV infection in these cases at time of detection being 15.9 years (range 9-23 years). Also within this group was a subgroup of 9 cases who had CD4+ T cell counts of less than 100 cells/Âµl at diagnosis with an average duration of HIV infection of 16.8 years (range 13.5 to 22 years).
LTNP, by definition means, an untreated HIV infected person without AIDS and with high CD4+ counts and low plasma viral loads, 7-10 or more years (as per different defining criteria) after infection, without ART. The stability of CD4+ cell counts â‰¥ 600 cells/mm3 versus â‰¥ 500 cells/Âµl has also been debated (2,7,8). The likely mechanisms for delayed progression appear to include a strong CD8+ cytotoxic T-lymphocyte and noncytolytic suppressive activity, host genetic factors including chemokine receptor polymorphisms, and infection with attenuated viral strains (7,9).
There is no single genetic determinant for non progression. Several genetic variants and mutations have been recognized to result in delayed progression of HIV disease. Heterozygosity for CCR5-32 deletion, the RANTES-28G mutation and CCR2-64I mutation and homozygosity for the SDF1-3'A mutation are some of the recognised mechanisms for delayed progression of HIV infection. CCR5 is the major co-receptor for R5 or macrophage-tropic strains of HIV. Thus, individuals homozygous for the CCR5-32 deletion are, with unusual exceptions, protected against HIV infection and the probable mechanism for slow progression in heterozygotes also becomes clear (4).
It is now established that CD8+ lymphocytes, play a central role in controlling both in vitro and in vivo HIV replication (10,11). The special subset of LTNPs has low viral loads, somewhat non virulent type of HIV when isolated, and mired virus propagation due to HIV antibody. They also have a more prevailing type 1 cytokines response as compared to type 2 with a strong CD8+ activity (12). It has been observed that CD8+ cells expressing CD28, CD95 are likely to be associated with long-term survival. Capability to produce Interleukins (IL) 2, interferon-gamma (IFN-Î³) and, to a lesser degree, IL-10 and IL-4, by purified CD8+ cells from LTNP patients, is retained (3). Thus, the immune-response in the LTNPs actively suppresses HIV proliferation, thus controlling the viral load at a relatively low level.
The concept of LTNPs and the variable patterns of morbidity and mortality can be better understood by delving into the history of the HIV infection. Divergent to the popular impression, the molecular chronometer of the HIV infection began in 1920-1940 when SIV in primates seems to have breached the human host (during accidental inoculation into human skin via blood ) from slaughtering of primates reared for food, in West Africa and evolution started around that time (6). There are many common genetic similarities shared by SIV and HIV as analyzed by molecular techniques. The cross-species contamination theory is supported by similarities in genomic structure, phylogenetic relatedness, prevalence in the natural host, geographic coincidence, and plausible routes of transmission (6). It has been theorized that at least three chimpanzee-to-human events created the HIV-1 M, N, and O groups, and at least seven sooty mangabey (primate)-to-human events led to the creation of HIV-2 groups (formerly known as subtypes) A through G (6). Paradoxically, the natural primate hosts of SIV, neither develop any AIDS-like disease nor any marked depletion of CD4+ T cells , despite the presence of very high viral loads. On the other hand when transmission of SIV occurs to unnatural hosts, such as the rhesus macaque monkey or humans, it causes a relentless depletion of CD4+ T cells with a high level of vulnerability to opportunistic infections. Studies of polymorphisms in major-histocompatibility-complex genes indicate that present-day primates having SIV infection (but no disease), may correspond to the survivors of an archaic retroviral pandemic (6).
As a corollary to the above, HIV infection is a zoonosis which manifests as AIDS due to a complex failure of adaptation between HIV and the host . Both mechanisms suggest that HIV and humans will eventually adapt and coexist, akin to the situation observed in natural SIV infection of primates (6). Nonetheless, the immunologic pressure against HIV in human hosts has steadily translated into population-dependent genetic changes in the virus genome. For example, the immunogenicity of regions of the virus that are potential targets for CD8+ T cells (restricted through the more common HLA class I alleles) has been widely removed from the pool of viruses circulating in the human population (8,13). A defective nef gene in HIV virus may impair virus replication; a R77Q change in the vpr gene reduces cellular apoptosis radically and critical changes at other HIV-1 genes such as vif, vpu or env may also account for the lack of progression in some HIV-infected persons (8). A high occurrence of defective nef alleles and defects in the long terminal repeat sequences (LTRS) have been found in long term survivors with nonprogressive human immunodeficiency virus type 1 infection (8,13,14). The means that the viruses in the contemporary times infecting people are already reflecting the changes of an evolving host-pathogen association.
This has resulted in a spectacular shift in mortality pattern within human populations worldwide. In 2006 it was estimated by the Joint United Nations Program on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) that there were 5.7 million people in India infected with the HIV. These figures were revised downwards to about 2.5 million in 2007 by the National AIDS Control Organization. These estimates were based on a more thorough representative sample extrapolated to the national scale, meaning thereby, that the epidemic in India is less widespread than earlier believed (15).
It is in this backdrop that our study also perhaps mirrors increasing survival with prolonged duration of HIV infection in the absence of treatment. The number of LTNPs in our study were 1.4-2.8% and LTSs were 3% of the total of 491 cases, which is in agreement with other documented studies. However, 11.6% cases (excluding LNTP) out of 491, i.e. 57 cases had HIV infection for a period ranging from 8 to 26 years (mean 16.2 years) with a mean CD4+ T cell count of 319 cells/Âµl at diagnosis. These patients were without treatment and without any evidence of opportunistic infection all these years till diagnosis, although later on during follow up almost half of them required ART as the eventual downhill progression of the disease is relentless except in the small group of LTNPs. Conventional teaching cites the average time from primary HIV infection to the development of AIDS in untreated individuals in the developed world to be about 10 years and much less in the developing world. The findings of our study could possibly reflect the shift in mortality patterns observed elsewhere in the world. Our study was limited by lack of facilities to evaluate host polymorphisms or to conduct viral genomic studies (for attenuated viral strains) .Whether it reflects an infection by less virulent/defective viral strains or changing host responses as part of evolutionary pressure of virus on host and vice-versa as suggested by the SIV model is still unclear. However it is clear that more people are surviving longer even without treatment and with a slower than expected rate of CD4+ T cell plunge.
Eradication of the HIV infection from the human population is not possible at this point of time because a pool of CD4+ T cells from which virus can be isolated persists in the majority of infected people despite containment of viremia by ART. This reservoir is long-lived, with a half-life of about 44 months, even after as many as 7 years of suppression of viral replication (6). It is likely that the latent reservoir is continually being maintained by undetectable levels of viral replication, even during effective ART.
The implications of longer survival (both natural evolution of disease and due to availability of better ART in future) will be that more number of HIV infected people will be surviving into the middle and older age groups, even in the developing countries. It is therefore logical to assume that there will be a higher prevalence of coronary artery disease, stroke, renal failure, osteoarthritis, osteoporosis, cataract, dementia,etc in these patients.
Less is known today about how these diseases will behave in presence of HIV/AIDS and ART. Apart from rising costs on health infrastructure, 'HIV Medicine' will have to be integrated in the teaching and experience of other subspecialties.