INTRODUCTION

Most evidence suggests that AIDS has it roots in Africa. This is believed because certain Simian Immunodeficiency Viruses (SIVs) are closely related to HIV-1 and HIV-2 (14) . The closest simian virus to HIV-1 discovered to date exists in certain chimpanzees(.15 )Although it has not been proven that HIV came from primates, an SIV has been known to infect humans(.16) The earliest evidence of HIV infection is that of an adult male who lived in the Democratic Republic of Congo. Researchers believe that the ancestor of this strain may date to the 1940s or 50s and was introduced into humans a decade or more earlier.(17) In June and July of 1981, cases of an extremely uncommon opportunistic infection, Pneumocystis carinii pneumonia, and a rare skin tumor , Kaposis sarcoma, were first reported in New York and California in epidemic proportions among previously healthy young homosexual and bisexual men(18)

By early 1982 the group of disease entities was named the acquired immune deficiency syndrome (AIDS) by the Center for Disease Control (CDC)(.17 )Since the appearance of the original definition in September of 1982, the CDC has subsequently revised this definition to accommodate additional syndromes recognized as manifestations of advanced HIV disease.(19) AIDS is caused by a previously unknown Human retrovirus, which was initially discovered and isolated in 1983 from patients with persistent generalized lymphadenopathy at the Institut Pasteur in Paris.(180 All the related viruses which were discovered were named the Human immunodeficiency virus (HIV) by the International Committee on the Taxonomy of Viruses in 1986.(18) CLASSIFICATION The current CDC classification system from the revision in 1993, combines three categories of the CD4 count with three symptom categories and is closer to a staging system but is still not described as such(.19)

CD4+ T-lymphocyte categories Category 1: > 500 cells/mm3 (or CD4% > 28%) Category 2: 200-499 cells/mm3 (or CD4% 14% 28%) Category 3: < 200 cells/mm3 (or CD4% < 14%) Categories of clinical conditions Category A Asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection in an adolescent (>13 years) with documented HIV infections. Conditions listed in categories B and C have not occurred. Category B Consists of symptomatic conditions in an HIV infected adolescent or adult that are not included among conditions listed in clinical Category C and that meet at least one of the following criteria: (a) the conditions are attributed to HIV infection or are indicative of a defect in cell mediated immunity; or (b) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection.

Category C Includes the clinical conditions listed in the 1993 AIDS surveillance case definition. For classification purposes, once a Category C condition has occurred, the person will remain in Category C.

Clinical A B C Categories/CD4+ T cell categories 1 A1 B1 C1 2 A2 B2 C2 3 A3 B3 C3 Persons in categories A3, B3, C1, C2 and C3 have AIDS under the 1993 surveillance case definition.

The median incubation period from HIV infection until development of AIDS is estimated at approximately ten years for young adults.22

Figure 1: Structure of the HIV virus

The integrated form of HIV-1 is known as the provirus. The genes of HIV are located in the central region of the proviral DNA and encode at least nine proteins. Structural proteins Gag proteins The gag gene gives rise to the 55 kilodalton gag precursor protein, also called p55, After budding, p55 is cleaved by the virally encoded protease during the process of viral

maturation into four smaller proteins designated MA (matrix [p17]), CA (capsid [p24]), NC (nucleocapsid [p9]), and p6. retrovirus.(24) The p24 (CA) protein forms the conical core of viral particles. (.25) The NC region is responsible for specifically recognizing packaging signal of HIV(.26 ) NC also facilitates reverse transcription.28 11 Gag-Pol precursor During viral maturation, the virally encoded protease cleaves the pol polypeptide away from gag and further digests it to separate the protease (p10), RT (p50), RNAse H (p15), and integrase (p31) activities. HIV-1 protease The HIV-1 protease activity is required for cleavage of the Gag and Gag-Pol polyprotein precursors during virion maturation. Reverse transcriptase The pol gene encodes reverse transcriptase. During the process of reverse

transcription, the polymerase makes a double stranded DNA copy of the dimer of single stranded genomic RNA present in the virion. Integrase The integrase protein mediates the insertion of the HIV proviral DNA into the genomic DNA of an infected cell. Envelope proteins A cellular protease cleaves gp160 to generate gp41 and gp120. gp41 contains the transmembrane domain of env, while gp120 is located on the surface of the infected cell and of the virion through non covalent interactions with gp41. env exists as a multimer, most likely a trimer, on the surface of the cell of the virion.30 Regulator proteins Tat Tat is a transcriptional transactivator that is essential for HIV-1 replication. .31 Rev Rev acts to induce the

transition from the early to the late phase of HIV gene expression. Accessory proteins Nef Nef causes the down regulation of the cell surface expression of CD4,34 the perturbation of T-cell activation,35 and the stimulation of HIV infectivity.36 Vpr Vpr plays a role in the ability of HIV to infect non dividing cells by facilitating the nuclear localization of the preintegration complex.37 Vpu HIV-2 does not contain vpu, but instead harbors another gene, vpx. 39 Vpu liberates the viral envelope by triggering the degradation of CD4 molecules complexed with Env.40 Vif Vif is essential for the replication of HIV in peripheral blood lymphocytes, macrophages, and certain cell lines.

TRANSMISSION Sexual transmission42 The current worldwide expansion of the AIDS epidemic is primarily driven by the sexual transmission of Human immunodeficiency virus type 1 (HIV-1) Sexual transmission among heterosexuals is the dominant mode of spread.43 HIV is commonly transmitted sexually by penile anal intercourse and penile vaginal intercourse and infrequently by fellatio. Vaginal intercourse can transmit HIV to either the male or the female partner, but risk is higher to the female partner.44 Use of zidovudine was associated with decreased detection of HIV-1 in semen.46 Injection drug use related HIV infection Transmission of HIV among injection drug users occurs primarily through HIV infected blood contamination of injections which is re-used by an uninfected injection drug users. Foremost among risk factors is the sharing of needles,

syringes, and other injection equipment. Sharing is a common practice among injection drug users worldwide.47 Transmission of HIV by blood, blood products, tissue transplantation and artificial insemination48 Transmission of HIV-1 and some other viruses can occur following transfusion of a blood product derived from an infected persons blood and processed into a blood component (i.e., whole blood, packed red cells, fresh frozen plasma, cryoprecipitate, and platelets).49 Vertical Transmission Perinatal transmission of human immunodeficiency virus accounts for virtually all new HIV infections in children.50 HIV testing Testing serum for antibodies to HIV with a standard ELISA (followed by a confirmatory Western Blot) is currently the most common, cost effective, and

accurate method of screening for infection.51 Rapid serum HIV antibody tests, saliva and urine-based antibody tests, and home HIV antibody testing kits have been approved by the Food and Drug Administration (FDA) and are being marketed.52 HIV RNA tests are being used in research and clinical settings to diagnose primary HIV infection before the formation of detectable antibodies.53 The replication Cycle of HIV-153

Figure 2: The replication cycle of HIV

8 Figure 3: HIV Life Cycle CLINICAL COURSE OF UNTREATED HIV DISEASE Primary infection Aborted HIV Infection

There is evidence that some individuals may successfully ward of infection after inoculation. Three different mechanisms are suggested. Defective co-receptor needed by HIV to infect cells. Immune response capable of preventing HIV from establishing infection. Mutation in the SDF-1 gene. Establishing Infection61 Spread of HIV to tissues and cells that ultimately may represent hard to eradicate viral reservoirs. Extensive damage to lymph node cellular architecture. Stimulation of an immune response against HIV.
Loss of HIV specific CD4+ and possibly CD8+ cell clones that may be effective in controlling HIV infection. Rapid HIV replication and mutation creating a more genetically diverse population of HIV genomes, some perhaps more virulent, or more fit for

replication in other micro environments such as in the presence of particular drugs or particular anti-HIV cytotoxic lymphocyte clones. Early Impact on T Cell Clones, T Cell Diversity, and Loss of Members of the T Cell Repertoire . One factor probably determining ultimate disease progression is the extent of very early destruction of the subpopulation of CD4+ T cell clones capable of recognizing HIV antigens. Loss of these clones means loss of the CD4+ T cell component of the natural anti-HIV immune response, which is crucial in controlling HIV replication.61 The Syndrome of Primary HIV Infection Most patients experience an acute syndrome within weeks of primary HIV infection and immune response. Syndrome commonly persists for several weeks.62 Early and Middle Stages of HIV Disease

Following the HIV antibody rise, levels of detectable virus, HIV RNA, and viral antigens in peripheral blood drop dramatically. This lower range, which is called set point, is relatively stable for months, perhaps years. Typically noted over this period is a drop in the CD4+ count, from normal levels to 200 to 300 cells/mm3. The frequently observed generalized lymphadenopathy syndrome is probably a manifestation of this process, although why lymphadenopathy is prominent only in some patients remains uncertain.63 Advanced HIV Disease Untreated patients with manifestations of advanced HIV disease typically have CD4+ counts below 200 cells/mm3, increased plasma HIV RNA levels, and clinical manifestations indicative of severe immunocompromise, including conditions qualifying as CDC-defined AIDS. Opportunistic infections commonly occur.

Late-Stage HIV Disease

As the disease advances further and the CD4+ count drops below 50 cells/mm3, additional opportunistic infections as well as central nervous system non-Hodgkins lymphoma occur commonly, and, in homosexual males, existing Kaposis sarcoma may become extensive and cause disfigurement and clinically significant edema. Death eventually results from extensive disease of vital organs, most commonly the lungs, and presumably from effects of circulating toxins, electrolyte abnormalities, hematopoietic and circulatory failure, and autonomic nervous system damage. HEMATOLOGIC MANIFESTATIONS OF HIV INFECTION Clinically significant hematologic abnormalities are common in persons with HIV infection. Impaired hematopoiesis, immunemediated cytopenias, and altered coagulation mechanisms have all been described in HIV infected individuals. These

abnormalities may occur as a result of HIV infection itself, as sequelae of HIV-related opportunistic infections or malignancies, or as a consequence of therapies used for HIV infection and associated conditions. Anemia Anemia is a very common finding in patients with HIV infection, particularly in individuals with more advanced HIV disease. In a study of patients receiving no myelosuppressive therapies, 8% of asymptomatic HIV-seropositive patients, 20% of those with symptomatic middle-stage HIV disease, and 71% of those with Centers for Disease Control (CDC)-defined AIDS were anemic.(5) Investigation of a cohort from a longitudinal study of HIV disease found anemia in 18% of asymptomatic HIVseropositive patients, 50% of those with symptomatic middlestage HIV disease, and 75% of those with CDC-defined AIDS.(38) The Multicenter AIDS Cohort Study found that 3.2% of HIV-seropositive patients with mean CD4+ T lymphocyte counts of greater than 700 cells/mm3 were anemic, whereas anemia was present in 20.9% of

those with mean CD4+ T lymphocyte counts less than 249 cells/mm.3,65 HIV infection alone, without other complicating illness, may produce anemia in some patients. A study of serum immunoreactive erythropoietin in HIV-infected patients in various stages of illness showed that levels of the hormone failed to rise commensurately with increasing anemia, suggesting that insufficient amounts of erythropoietin may be one cause of anemia in this setting(64) Other studies have suggested that soluble factors in the serum of HIVinfected patients may inhibit hematopoiesis, or that direct HIV infection of marrow progenitor cells may play a role in producing anemia and other hematologic abnormalities associated with HIV infection.66,67

NAME OF STUDY

YEAR

Spivak J K et al

1984

n % of ANAEMIA HIV AIDS 18 75

Frontiera M et al Zon li et al Groopman je et al Manisha et al Kasthuri AS et al Attili et al Sara Jam et al Byomakesh Dikshit et al Akinsegun Akinbami et al

1987 1988 1988 2002 2006 2008 2009 2009 2010 106 106 416 100 430 642 200 205 42 20

95 70 63- 95 90.8 61

65.5 24.2

Drug-Induced Anemia Zidovudine (AZT) therapy is probably the most common cause of anemia in HIV-infected patients. In the original phase II clinical trial that demonstrated the

efficacy of AZT in patients with advanced HIV disease, statistically significant reductions in hemoglobin levels occurred in 34% of subjects receiving AZT (1,200 mg per day) following six weeks of therapy(68 )accompanied by a progressive rise in erythrocyte mean corpuscular volume Thirty-one percent of AZT-treated subjects in the trial required red blood cell transfusions while receiving the drug. Marrow erythroid hypoplasia, aplasia, and megaloblastic maturation have developed as a result of AZT therapy. Subsequent studies have demonstrated that anemia is less common in patients with relatively less advanced HIV disease and in those receiving reduced dosages of AZT; for example, clinically significant anemia (hemoglobin < 8 g/dl) occurred in only 1.1% of asymptomatic HIV-infected patients with 200 to 500 CD4+ T lymphocytes/mm3 treated for a mean of 55 weeks with AZT (500 mg/day)(.69) More recent studies of combination antiretroviral therapy have confirmed the relatively low incidence of severe anemia at lower doses of zidovudine.(70)

Effective therapy for AZT-induced anemia is available in the form of recombinant human erythropoietin. A doubleblind, placebo-controlled study demonstrated that recombinant human erythropoietin (100 units/kg three times weekly by intravenous bolus) reduced transfusion requirements of AZT-treated HIV-infected patients whose serum levels of endogenous erythropoietin were less than 500 IU per liter.(71) Antimicrobial and antineoplastic agents used for treatment or prophylaxis against HIV-related conditions also cause anemia. For example, Dapsone for treatment or prevention of Pneumocystis carinii pneumonia (PCP) may cause hemolytic anemia or generalized myelosuppression,72 and anemia routinely occurs when myelosuppressive chemotherapy is used to treat HIV related non-Hodgkins lymphoma. Anemia Caused by Bone Marrow Infections Infection with Mycobacterium avium complex (MAC) is another common

cause of anemia in advanced HIV disease. This infection, diagnosed in up to 18% of patients with advanced HIV disease during the course of their illness,(73) causes high-grade bacteremia and widely disseminated infection, usually involving the bone marrow. In such patients, anemia tends to occur out of proportion to other cytopenias. The benefit of the antimycobacterial therapies currently available for MAC infection is controversial. Although some treatment studies have demonstrated a reduction in symptoms, such as fever, in conjunction with a reduction in the number of organisms in the blood, no study of antimycobacterial therapy for MAC infection has shown improvement of the associated anemia. Infection with B19 parvovirus can also cause anemia in HIV-infected patients.74,75 B19 parvovirus, the etiologic agent of the childhood exanthem fifth disease (erythema infectiosum), has been recognized for sometime as a cause of severe chronic anemia in immunocompromised persons. Parvovirus DNA has been

detected in the serum or bone marrow (or both) of some patients with HIV infection and severe anemia. The anemia of parvovirus infection has been successfully treated with infusions of immunoglobulin (400 mg/kg/day over 5 to 10 days). Tuberculosis, histoplasmosis, cryptococcosis, pneumocystosis and nonHodgkins lymphoma can all infiltrate the bone marrow, generally causing pancytopenia. Other causes of anemia Antierythrocyte antibodies produce a positive direct antiglobulin test in approximately 20% of HIV-infected patients with hypergammaglobulinemia.75 Hemolytic anemia in the setting of an HIV-related positive direct antiglobulin test is rare. Gastrointestinal bleeding should also be considered in the evaluation of HIV-infected patients with anemia. In addition to the usual causes of gastrointestinal blood loss, HIV-related infections such as cytomegalovirus colitis and malignancies such as Kaposis sarcoma and non-Hodgkins lymphoma may produce clinically

significant bleeding. Hypogonadism is relatively common in HIVinfected men, and the associated symptoms and problems (fatigue, weight loss, sexual dysfunction) may also include 26 anemia. A serum testosterone level should therefore also be included in the evaluation of men with anemia and other symptoms suggestive of possible hypogonadism. . Pancytopenia The pancytopenia frequency in a cohort of 147 HIV seropositive subjects (39 adults and 108 children) during 10 years was evaluated to 15%, meaning an incidence of 1,5/100 pers/year (18% in adults and 14% in children). Significant differences (p < 0.001) was observed, between the frequency of pancytopenia to the subjects having a number of Ly T CD4+ < 200/mm3 (37.5%), and the frequency to the subjects with a number of Ly T CD4+ 200-400/mm3 (11%) . The mains identified mechanisms were:

1. HIV infections of the bone marrow CD34+ population. 2. Viral persistence infection of stem cells, and stromal cells (EBV, PV-B19, CMV, HHV8, HTLV I, II). 3. Disturbance of cytokines and interleukins synthesis and activity. 4. Bone marrow involvement by lymphoma, Kaposi's angiosarcoma and granulomatous disease. 5. Myelotoxic effects of ARV-therapy. The main diagnosed entities were: Pancytopenia by bone marrow aplasiahypoplasia in 13.63%. Pancytopenia with myelodysplastic changes in 31.82%. Pancytopenia with hemophagocytic syndrome in 13.63%. Pancytopenia by bone marrow involvement in lymphoma and Kaposi's angiosarcoma secondary to infection with opportunistic oncogenic virus (EBVLMNH, HHV8-Kaposis angiosarcoma) in 13.63%. Pancytopenia secondary to infections involving the bone marrow e.g.

Mycobacterium avium intracellulare, Mycobacterium tuberculosis, Toxoplasma Gondii, Histoplasma Capsulatum, Cryptococcus, Leishmania Donovani, bone marrow necrosis (27%). Thrombocytopenia Thrombocytopenia is frequently associated with HIV infection. In the Multicenter AIDS Cohort Study, platelet counts were measured in over 1,500 HIV-seropositive participants who did not have CDC-defined AIDS; 6.7% of participants had platelet counts of less than 150,000 cells/mm3 on at least one semiannual visit, and 2.6% of participants had platelet counts of less than 150,000 cells/mm3 on two successive semiannual visits. In a Swiss study, platelet counts of less than 100,000 cells/mm3 were noted in 9% of 321 HIV-seropositive injection drug users and in 3% of 359 HIV-seropositive homosexual men. A smaller study from London reported platelet counts of less than 150,000 cells/mm3 in 30% (6 of 20) of patients with advanced HIV disease and 8% (5 of 59) of patients with persistent generalized lymphadenopathy.76

Possible etiologies of thrombocytopenia in patients with HIV infection include immune-mediated destruction, thrombotic thrombocytopenic purpura, impaired hematopoiesis, and toxic effects of medications. In many instances, however, thrombocytopenia is a relatively isolated hematologic abnormality associated with a normal or increased number of megakaryocytes in the bone marrow and elevated levels of platelet-associated immunoglobulin. These patients have the clinical syndrome commonly referred to as immune thrombocytopenic purpura (ITP). deposited on platelet membranes, resulting in reticuloendothelial clearance. Studies have shown that these immune complexes contain anti-HIV gp120 and complementary anti-idiotypic antibody. The hypothesis that a specific antiplatelet antibody binds to the platelet membrane, resulting in platelet destruction, has fallen out of favor. Another theory is the direct infection of megakaryocytes by HIV may impair

platelet production and contribute to thrombocytopenia.78 NAME OF STUDY Zon Li Murphy MF et al. Jost j etal Kaslow RA et al Kasthuri AS et al ATTILI et al Akinbami et al Arora et al YEAR 106 n 106 105 321 1411 2006 2008 2010 2011 100 430 205 50 LEUCOPENIA % 40 30 9 6.7 80 4.8 16.10 18

Other causes of thrombocytopenia in HIV infection

Any of the infectious or neoplastic conditions that involve the bone marrow and any of the medications that cause generalized myelosuppression in patients with HIV infection can produce thrombocytopenia. HIV-infected patients are also susceptible to developing thrombocytopenia for reasons unrelated to their HIV infection, such as alcohol use, splenomegaly and liver disease, or drug effects (heparin, quinidine) 31 . Granulocytopenia and Abnormal Granulocyte Function Granulocytopenia is a problem commonly encountered in patients with HIV infection. Although low granulocyte counts usually reflect the toxicity of therapies for HIV infection or associated conditions, studies of untreated patients have also shown a high incidence of granulocytopenia, particularly in patients with more profound immunodeficiency. For example, the Multicenter AIDS Cohort Study found that 0.8% of HIV-seropositive patients with mean CD4+ T lymphocyte counts of greater than

700 cells/mm3 had abnormally low granulocyte counts, whereas granulocytopenia was present in 13.4% of those with mean CD4+ T lymphocyte counts below 249 cells/mm3.65 Zon and Groopman noted low granulocyte counts in 13% of asymptomatic HIV-seropositive patients and in 44% of those with frank CDC-defined AIDS.5 The pathogenesis of granulocytopenia in patients with HIV infection is multifactorial. An autoimmune mechanism involving antigranulocyte antibodies83 and impaired granulopoiesis40,.41 has been postulated. Any infiltrative process involving the bone marrow (infection, malignancy) may also produce granulocytopenia. In clinical practice, however, drug toxicity is responsible for most of the granulocytopenia seen in patients with HIV infection. It is important to note that in one study, investigators showed a good correlation between the level of the absolute granulocyte count and the risk of 33

hospitalization for a significant bacterial infection in weeks immediately following the absolute neutrophil count (ANC).80 Drug-Induced Granulocytopenia AZT therapy is probably the most common cause of low granulocyte counts in patients with HIV infection. Severe granulocytopenia (< 500 cells/mm3) developed in 16% of AZT-treated patients in the original placebo-controlled study of AZT therapy for advanced HIV disease and symptomatic middle-stage HIV disease; only 2% of placebo-treated patients became granulocytopenic to this degree.42 Despite the relatively high frequency of AZT-induced granulocytopenia, there were no reported episodes of bacterial infection or sepsis in the study group. In subsequent studies of AZT therapy,43 the observed risk of bacterial infection was low, reflecting the brief duration of AZT-induced granulocytopenia; the dosage of AZT was reduced or discontinued when the granulocyte count fell below the range of 500 to 1,000 cells/mm3. Shaunak and Bartlett described their experience in treating 30 patients with

severe, recurrent (three or more episodes) AZTinduced granulocytopenia.81 Ganciclovir therapy for symptomatic cytomegalovirus infection is another common cause of granulocytopenia in patients with advanced HIV disease. Jacobson et al. observed absolute granulocyte counts of less than 800 cells/mm3 in 10 of patients receiving chronic daily maintenance ganciclovir therapy. Granulocytopenia has been reported patients receiving trimethoprimsulfamethoxazole, pentamidine and interferon-alpha therapy. Antineoplastic chemotherapy is probably the most common cause of low granulocyte counts in patients without HIV infection. Granulocytopenia secondary to cancer chemotherapy also complicates treatment of HIV-infected patients, perhaps to an even greater extent as a result of impaired bone marrow function. In summary, drug-induced granulocytopenia is common in patients with HIV infection. When the granulocyte count falls below 500 cells/mm3, the risk of infection

and sepsis is significant. Empiric antibiotic therapy are reserved for these situations in which frank evidence of bacterial infection is present, or the granulocyte count is below 500 cells/mm3. NAME YEAR OF STUDY n % OF GRANULOCYTOPENIA

Lymphopenia Increases in both CD4 andCD8 cell death and impairment in function are the sine qua non of HIV infection. IL-2 partially corrects the impaired lymphocyte proliferation and cytotoxicity seen in HIV infection. It also can partially block the enhanced tendency of lymphocytes obtained from HIV-infected patients to undergo

programmed cell death.83 NAME OF YEAR STUDY Frontiera 1987 M et al Akinsegun 2010 Akinbami et al n % LYMPHOPENIA 76 26.8

CD4+ T Cells Progressive depletion in numbers of circulating CD4+ T cells occurs in almost all cases of untreated HIV infection. The number of circulating CD4+ T cells is widely used as a measure of global immune competence and provides a predictor of the immediate risk for opportunistic illnesses.84 Earlier in the course of infection,

many HIV-infected persons have a syndrome of generalized lymphadenopathy characterized by accumulation of lymphocytes within inflammatory lymph nodes and upregulation of adhesion molecule expression. Early in the course of infection, memory CD4+ T cells are selectively depleted from circulation; as disease advances, CD4+ T cells of both the nave and memory phenotype are lost from circulation.85 In advanced disease, all CD4 cell populations are depleted from circulation and from lymphoid tissue sites. Functional abnormalities of CD4+ T cells are also characteristic of progressive HIV infection. Failure of CD4+ lymphocytes to undergo cell division, for example, has been demonstrated following stimulation of T cells from infected individuals with antigens or mitogens in vitro. A sequential loss of immune responsiveness to recall antigens, followed by alloantigens and then mitogens has been described. Diminished expression of IL-2 is readily demonstrable.86,87 In cells from HIV-infected individuals and may be related to the proliferation defects. In contrast, expression of interferongamma

by these cells is often unimpaired,87 suggesting that the defective responsiveness is not a consequence of depletion of antigen-reactive cells but rather a selective impairment in the ability of these cells to respond after engagement of TCRs. The function of CD4+ T cells that specifically recognize antigens from HIV itself appears to be selecxtively impaired early in the course of HIV infection. Using anti-TCR antibody stimulation to characterize proliferation defects in CD4+ T cells indicates that proliferation defects in HIV disease are associated with early G1-phase cell-cycle arrest88 and are more commonly observed in persons who have experienced sustained CD4 cell losses.89 As a key role of CD4+ T cells is to facilitate immune response though production of immunomodulatory cytokines, the loss of these cells and the failure of remaining cells to function properly constitutes a critical impairment in immune capability. Specific CD4+ T-cell responses to HIV antigens appear to be selectively and lastingly impaired during early HIV infection.

However, the exact mechanisms by which HIV causes the loss of CD4+ T cells are still unknown, and other cell lines such as CD8+ T cells, which are presumably resistant to HIV infection are also diminished over the course of infection. Any or all of the following mechanisms may contribute to CD4+ T cell loss, including: virusmediated cell killing, immune-mediated cell killing, chronic activation leading to the premature death of uninfected cells, generation of auto-antibodies and impaired CD4+ T cell production. Cells of the monocyte/macrophage lineage represent the other major target of HIV infection, but these cells are relatively unaffected by HIVs cytopathic effects. CD8+ T Cells In early HIV infection, CD8+ T-cell numbers tend to increase, reflecting expansion of memory CD8+ T cells, particularly HIV-reactive cells. CD8 cell expansions persist until far advanced stages of HIV disease, when all T-cell numbers tend to fall.90 In contrast to memory CD8 cell expansions, proportions of naive

CD8 cells tend to fall in early infection, but absolute numbers of these cells do not fall until HIV disease progresses.85 For example, in earlier disease CD8+ T cells that recognize cytomegalovirus are present in large numbers, but in advanced disease the cytolytic function of CD8+ T cells directed against opportunistic pathogens is demonstrably impaired.91 It is not entirely clear whether the CD8+ cells present in early disease are functionally normal, as the maturation phenotype CD8+ T cells recognizing pathogen-derived peptides has been found to be variably perturbed.92 Whether this is the cause or the consequence (or the interaction of both) of greater exposure to opportunistic pathogen-derived antigens in HIV-infected immunosuppressed persons is difficult to sort out. As is seen with CD4+ T cells in HIV infection, CD8+ T cert! obtained from HIV-infected persons may fail to proliferate in response to TCR activation in vitro.93 In this setting, however, it is not clear whether the failure to proliferate is a

consequence of failure of CD4+ T-cell help (via provision of IL-2 that is essential for CD8+ T-cell proliferation), a reflection of an intrinsic failure of CD8+ T-cell function, or a consequence of CD8+ T-cell maturation to a predominantly effector phenotype. As with cellular immune responses, the humoral immune system in HIV infection is characterized by paradoxical hyperactivation and hyporesponsiveness. Hyperactivation is reflected in dramatic polyclonal hyperglobulinemia, only a portion of which is directed against HIV antigens;94 bone marrow plasmacytosis;95 heightened expression of activation molecules on circulating B lymphocytes;96,97 the presence of autoreactive antibodies in plasma;98 and instances of clinical autoimmune-like disease. B-cell hyper-reactivity may contribute to the increased risk of B-cell lymphomas in HIV-infected persons, but no causal link has been clearly established.99 Neither is the etiology of hyperglobulinemia well understood. Elevated plasma levels of the endogenous B-lymphocyte stimulator have been found in HIV-infected 38

persons100,101 and this may contribute to the Blymphocyte activation of HIV infection and AIDS. At the same time, diminished Blymphocyte responsiveness to antigenic stimulation in vitro is characteristic of HIVinfected persons,102,103,104 who often fail to develop protective antibody responses after immunization with protein or with polysaccharide vaccines.105,106,107,108 The characterization of antibody responses to polysaccharides as T-cell independent is only partially correct. Although antibodies can be induced to polysaccharides in the absence of linked peptides that induce cognate help by proximate CD4+ T cells, these responses are not optimal. Moreover, B-lymphocyte responses to pure sugars still require some degree of T -helper support. Lack of CD4 help may therefore underlie the poor antibody responses to polysaccharides that are seen in HIV infection.

Hemostatic Abnormalities Thrombosis reportedly occurs in upto 2% of HIVinfected patients. Factors

associated with venous thromboembolic complications include age over 45 years, advanced stage of HIV infection, the presence of CMV or other AIDS-defining opportunistic infections, hospitalization, and therapy with indinavir or megestrol acetate.109 The association between opportunistic infections and thrombosis may simply reflect immobility due to illness. CMV may promote adhesion of neutrophils and platelets to the endothelium, induce production of antiphospholipid antibodies, enhance synthesis, and increase secretion and survival of factor VIII and Von Willebrand factor.110 39 Megestrol, like other progestational agents may cause, acquired resistance to activated protein C.111 In addition, individuals with HIV infection may be at increased risk for thrombosis because of decreased levels of antithrombin III, free protein S, protein C, or heparin cofactor II; the presence of anticardiolipin antibodies; coexistence of

malignant, inflammatory or autoimmune disorders; or vascular damage due to infection, drug use, placement of intravenous catheters, or CMV infection.112 Antithrombin III deficiency can occur in association with HIV nephropathy as a result of losses in the urine. The nephrotic syndrome seen in HIV nephropathy may also result in compensatory hepatic synthesis of factors V, VIII and X induced by hypoalbuminemia, and increased platelet adhesion and aggregation.113 Acquired protein S deficiency can be found in upto 75% of HIV-infected children and adults, especially in patients with CD4 counts below 200/ l or AIDS, resulting in thrombotic complications in as many as 12%.114 Acquired free protein S deficiency in HIV is due to appearance of antibodies against protein S.115 The levels of free protein S antigen in HIV patients can appear artificially low when assayed by the PEG precipitation technique, so that the prevalence of protein S deficiency in HIV-positive patients may actually be lower than previously thought (about 10%).116

The lupus anticoagulant is found in 0%-70% of patients with HIV infection, depending on the sensitivity of the assay and the characteristics of the patient 40 examined. Anticardiolipin antibodies are detected in 46%-90% of these patients.117,118,119 The bone marrow in Human Immunodeficiency Virus (HIV) Infection Morphologic abnormalities can be found in the majority of bone marrow samples from HIV-1 infected patients, but most are non-specific except in opportunistic infections, in which the bone marrow examination provides valuable diagnostic information. Therefore, the bone marrow examination rarely yields substantial clinical information, except in the diagnosis of concurrent M. avium intracellulare, tuberculosis, or fungal infection or as part of staging for malignancy.120 The histopathologic findings in the bone marrow of HIV-1 infected patients are varied which includes hypercellular marrow, myelodysplastic changes,

hypocellular marrow and fibrosis of bone marrow.120 Hyperplasia involving the granulocytic and erythrocytic lineages has been reported: the myeloid to erythroid ratio has varied from 2:1 to 5:1.121 The morphologic changes tend to be more pronounced in more immunocompromised patients and increase in frequency as disease progresses. All lineages can be involved.122,123 Megaloblastic changes and dysplastic changes, ringed sideroblasts are frequent. The cumulative effects of drug toxicities, direct HIV-1 infection ofmarrow cells, and dysregulated cytokine production may be responsible for the morphologic changes that occur late in AIDS.
MATERIALS AND METHODS

Patients detected to be HIV positive as per who criteria attending to Dept. of Medicine and its ART centre ( above 14 years) CRGH , Ujjain were taken up for study.

SAMPLE SIZE - One hundred patients. SAMPLE DESIGN SAMPLING METHOD sampling STUDY AREA

Cross sectional study Simple random

Ujjain

INCLUSION CRITERIA :

HIV positive patients attending ART centre ( above 14 years ) and Dept. of Medicine , CRGH, Ujjain.
EXCLUSION CRITERIA :

1. Patients with known hematologic disorders. 2. Congenital hematological disorders. 3. Under 14 years visiting art centre. 4. Pregnant females . 5. Patients taking bone marrow suppressive drugs.

Data was collected by using pretested proforma meeting the objectives of the study. Purpose of the study was explained to the patient and consent was taken.

All patients were interviewed , detailed history was taken with respect to risk factors and detailed physical examination was carried out. Appropriate investigations were done.

1. Complete hemogram including peripheral smear. 2. Bone marrow biopsy whenever indicated. 3. CD4 lymphocyte count by flow cytometry using standard technique 4. Lymph node biopsy , USG abdomen ,CT scan /MRI if needed. The results were analysed by standard statistical methods using SPSS 17 Software.

The results were analysed by calculating percentages, the mean values, standard deviation, Chi-square t test and proportion test. Proportions were compared using Chi-square test of significance. A p value of less than 0.05 was considered statistically significant.

. Figure 4: Becton and Dickinson Flow Cytometry FAC Scan

CONCLUSION In the present study, out of 100 patients, the commonest haematological manifestations found were anemia, leucopenia and thrombocytopenia.. The frequency and severity of these hematological manifestations increased with

decline in CD4 count and had got significant impact on clinical outcomes and quality of life. Hence all HIV patients should be investigated for hematological abnormalities and treated accordingly to reduce morbidity and mortality. SUMMARY Peripheral and bone marrow abnormalities are common in HIV related disease and has got significant impact on clinical outcomes and quality of life (QOL). The variation in the prevalence of hematological abnormalities in different stages of disease are due to number of factors which includes CD4 count, clinical disease status, drug therapy, opportunistic infections and malignancy. HIV infection affected the highly productive age group of 21-40 years of age (74%) and predominantly males (80%) in the present study. The most common symptom was fatigue (86%) and fever (80%), and among the

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83 PROFORMA Patient information Name : IP/ART No. Income: Age : Sex: DOA: DOD: Occupation: Address: Diagnosis: Symptoms Fever : Yes / No Dyspnoea : Yes / No Fatigue : Yes / No Palpitation : Yes / No Bleeding : Yes / No Cough : Yes / No Weight loss : Yes / No Diarrhoea : Yes / No Jaundice : Yes / No Miscellaneous: Yes / No Anorexia : Yes / No Past history Pregnancy/Postpartum : Associated illness : Past history : Medications : Examination Pulse : Pallor : Emaciation: Edema: BP : Icterus : Oral thrush: Bitot: RR : Cyanosis: Lymphadenopathy: Temp : Clubbing: Petechiae/Purpura 84 CVS : RS :

CNS : PA : Complete blood count Hemoglobin : Total count : Hematocrit : Platelet count : Reticulocyte count : ESR : Differential count : RBC indices MCV : MCHC: MCH : RDW : Reticulocyte index: Cell morphology Cell size : Poikilocytosis: Hb content : Polychromasia: Anisocytosis : Miscellaneous: Nuclear segmentation of neutrophils: Bone marrow aspirate M/E ratio : Cell morphology : Iron stain : 85 Bone marrow biopsy Cellularity : Morphology : CD4 count : CD4/CD8 ratio : CD8 count : ALC : Miscellaneous

86 CASE NO. 1 A 36 year old male patient, tailor by occupation, presented with history of fever since 2 weeks, history of easy fatigability, history of weight loss > 10%, history of diarrhoea since 2 weeks. Past history: Patient was diagnosed to be immunocompromised since 2 years, on right with ART since six months. O/E Pallor present, oral thrush present Pulse: 90/min, BP: 110/70 mmHg, RR: 22/min Temperature: 39tF CVS: S1 S2 heard, No murmurs RS: Trachea shifted to left side. Decreased chest movements left supraclavicular, infraclavicular, suprascapular and axillary areas. Cavernous breath sounds present in above said areas. Five crests present in the above areas. P/A soft, CNS: Patient conscious, alert Investigation: Hb% 12.9 gm%, Haematocrit 43.9% Total leucocyte count: 1900, DC N 73%, l 16%, M3 E4 B4 Plate count: 1.1 lakh/mm3, ESR: 30 mm/hr

Peripheral smear: Normocytic normochromic anemia CD4 count: 36; CD8 count: 460; CD4:CD8: 0.08 Chest X-ray PA view: Left upper zone fibrosis Sputum AFB 1 2 Positive 3 87 CASE NO. 15 A 32 year old male patient, coolie by occupation, presented with history of fever since 3 weeks, cough since 3 weeks, exertional breathlessness since 2 weeks. O/E Pallor present, central cyanosis present Pulse: 102/min, BP: 104/70 mmHg, RR: 26/min Temperature: 39.4tF CVS: S1 S2 heard, ESM present, pulmonary area RS: NVBS present, Occasional crepts present. P/A Soft CNS: Patient conscious, alert Investigation: Hb% 8 gm%, Haematocrit 23.1% Total leucocyte count: 6600 cells/mm3, DC N 89%, L 8.8%, M 0.5 E2 Plate count: 70,000/mm3, ESR: 70 mm/hr Peripheral smear: Normocytic normochromic blood picture Bone marrow biopsy: Normoblastic blood pricture. CD4 count: 55; CD8 count: 1094; CD4:CD8: 0.05

Chest X-ray PA view: NRA 88 CASE NO. 50 A 35 year old male patient, agriculturist by occupation, presented with history of cough with expectoration since two months. O/E Pallor present Pulse: 96/min, BP: 120/80 mmHg, RR: 26/min Temperature: 39tF CVS: S1 S2 heard, No murmurs RS: Trachea shifted to right side. Cavenous breath sounds present, right supraclavicular, infraclavicular, supracapsular and axillary areas. Crepitations present in the above said areas. P/A soft CNS: Patinet conscious, alert Investigation: Hb% 10.4 gm%, Haematocrit 44.6% Total leucocyte count: 2600/mm3, N 54 L 32 M 2 F2 Plate count: 2.4 lakh/mm3, ESR: 10 mm/hr Peripheral smear: Dimorphic anemia Bone marrow biopsy: Normoblastic marrow CD4 count: 236; CD8 count: 680; CD4:CD8: 0.17 Chest X-ray PA view: Right upper zone fibrosis Sputum AFB 1 2 Negative

3 89 CASE NO. 57 A 30 year old male patient, tailor by occupation, presented with history of cough with expectoration since one month, easy fatigability one month O/E Pallor present, oral thrush present Cervical lymphadenopathy present, B/L lower limb pitting pedal edema Pulse: 102/min, regular BP: 144/70 mmHg Temperature: 39tF CVS: S1 S2 heard, No murmurs ESM present, pulmonary, tricuspid area RS: NVBS present P/A Soft CNS Patient conscious, alert Investigations: Hb% 6.4 gm%, Haematocrit 36.5% Total leucocyte count: 3000/mm3, N 54, L 43 E 1 M1B1 Plate count: 80,000/mm3, ESR: 50 mm/hr Peripheral smear: Pancytopenia Bone marrow biopsy: Hypocellular marrow Chest X-ray PA view: NRA CD4 count: 21; CD8 cont: 560; CD4:CD8: 0.04 90

CASE NO. 76 A 35 year old male patient, agriculturist by occupation, presented with history of exertional breathlessness since one month generalised weakness since one month. O/E Pallor present Pulse: 102/min, regular BP: 120/80 mmHg, RR: 20/min Temperature: 39tF CVS: S1 S2 heard, No murmurs RS: NUBS present No added sounds P/A Soft No organised Investigation: Hb% 8.6 gm%, Haematocrit 41% Total leucocyte count: 2400/mm3, N 42%, L 53 M2 E 3 Plate count: 90,000/mm3, ESR: 55 mm/hr Peripheral smear: Pancytopenia Bone marrow biopsy: Normoblastic marrow CD4 count: 34; CD8 cont: 369; CD4:CD8: 0.09 Chest X-ray PA view: NRA 91 KEY TO MASTER CHART A Agriculture ART Anti retroviral therapy ATT Anti tubercular treatment B/L Bilateral

C Coolie C/S Clinical stage CNS Central nervous system CVS Cardiovascular system DA Dimorphic anemia F Female Fe Febrile HC Hypocellular marrow HP Hypercellular marrow HTN Hypertension LP Left sided pleural effusion LUF Left upper lobe fibrosis M Male MHA Macrocytic hypochromic anemia MTB Miliary tuberculosis N No or Normal NAD No abnormality detected NB Normoblastic marrow NHA Normocytic normochromic anemia NNA Normocytic hypochromic anemia P/A Per abdomen PA Pancytopenia PL Pleural effusion PTB Pulmonary tuberculosis PUO Pyrexia of unknown origin RLLC Right lower lobe consolidation RMC Right middle lobe consolidation

RS Respiratory system RUF Right upper lobe fibrosis T Tailor TBL Tubercular lymphadenopathy Y Yes Sl. No. Name IP/ART No. Age Sex Occupation Diagnosis Fatigue Fever Weight loss Jaundice Dyspnoea Anorexia Cough Diarrhoea Palpitation Miscellaneous Associated illness Medications Pulse/mm Bp Temperature

Pallor Clubbing Cyanosis Emaciation Oral thrush Adenopathy Edema Petechiae parpura CVS RS PA CNS Hb% Haematocrit Total count Neutral count (%) Lymphocyte count (%) Monocytes (%) Eosinophils (%) Basophytes (%) Platelet count ESR Peripheral smear Bone marrow study CD4 CD8

1 Raju 1452 36 M T PTB + + + - + + - + - - - ART 90 110/70 39 - - - - + - - - - LUF - - 12.9 13.6 1900 63 16 30 2 0 1.1 30 NNA - 36 460 2 Kumar 1609 27 M G CSI + + - - - - + + - - ART 86 120/70 39 - - - + + + + + - - - - 14.1 15.2 2800 38 14 1 6 3 1.3 40 NNA - 197 1264 3 Bharthi 1580 28 F H Hapes + + - - - + - + - VD Herpes ART 90 110/70 39 - - - - - - - + - - - - 11 42.4 2200 50 11 0.5 8 1.5 1.8 42 NHA - 677 2140 4 Siddegowde 1614 32 M A Pwo + + + - - - + + - - N 98 100/70 39 + + + + - + - - - - S - 9.1 39.2 6000 76 9.4 4.6 6 2 1 36 NHA - 9.48 92.1 5 Hansaraj 1406 34 M S T + + + - + + + + + - - N 80 110/70 39 + - - + + + - + - RLLC S - 14.5 45 2600 66 11 2.7 7.3 2 1.7 65 NNA - 47 370 6 Jyothi 1285 29 F A Pao + + + - - - - + - - - N 102 120/80 39 + - - + - - - - - - - - 9.6 39 7700 76 18 2 4 0 1.2 110 NHA - 41 189 7 Manjunath 442 31 M A E + + + - - - + - - - - N 110 106/70 40 + - - + - - - - - - S - 8 38 4600 53 26 6 12 2 0.9 85 NHA - 15.8 785 8 Khalid Ahmed 1668 38 M C CS III + + + + + + + + - - - N 102 110/60 40 + - - - - + + - - - - - 9.7 29.8 4200 67 19 4.4 8.2 1.4 1.7 88 NHA - 13 410 9 Ninge Gowda 1705 44 M A CS III + + + - + + + - - - - N 100 100/70 40 + - - + - - - - - RMC - - 11 44 10000 89 9 1 1 0 1.2 150 NNA - 36.1 1048

10 Sugana 93978 25 F Hw CS III + - + - + + + - - - N 100 100/70 39 + - - + + - - + - - - - 9 40.2 3300 86 13 0 2 0 0.8 80 NHA - 29 170 11 Lingarajamma 3643 30 F A CS III + + + - + - + - + - - N 80 110/70 39 - + + + + + + + - - - - 11.5 31.9 9100 82 8.7 1 4 1 4 14 NNA - 25 175 12 Shivaling Naika 3608 45 M C CS II - - -- - - - - - - - N 86 120/80 39 - - - - - - - + - - - - 11.5 33.5 7500 58 19 2 4 2 4.2 22 NHA - 283 2008 13 Pravathi 3611 35 F C CS I + - - - - - - - - - - N 90 110/70 39 + - - - + - - - - - - - 11.2 32.4 5500 66 29 2 2 1 2.9 35 NNA - 159 710 14 Sarasamma 3638 52 F Hw CS II + + + - + + - - - - N 100 120/80 39 + - - + + + - - - - - - 8.3 25.8 5000 64 29 2 4 1 3.6 100 NHA - 360 2008 15 Manjunath 3450 32 F C CS II - + - - + + + + + - N 102 104/70 39 - - + + - - - - - - - - 8 23.1 6600 89 8.8 0.5 2 0 0.7 70 NNAE NB 55 1094 16 Madappa 3645 28 M S CS III + + + + + + + + - - N 90 110/70 40 - - - - - - - -- - - - - 12.8 36.9 2300 60 10 3 5 2 2.7 60 NNA NB 89 707 17 Chandrashakar 3448 38 M A CS I + - - - - - - - - - N 100 126/80 39 + - - + + + + - - - - - 16.1 45.4 5300 61 30 3 4 1 1.9 25 NHA - 244 899 18 Rajanna 1436 47 M A CS I + - + - - - - - - - - N 96 140/86 39 + - - - - - - - - - - - 14.4 40.7 10000 56 39 1 3 2 2.6 36 NNA - 166 1720

19 Lakshmi 3548 26 F C CS I - - + - - - - - - - - N 98 120/80 39 - + + + + + - - - - - - 12.7 34.3 11900 58 36 6.5 6.5 1 3.1 16 NhA - 1041 868 20 Beeregowda 3614 26 M A CS II + - + - + + - - - - ART 88 110/70 39 + - - + + - - - - - - - 13.5 37.7 10500 64 15 3 10 2 2.1 22 NNA - 129 4.35 21 Mahesh 3629 30 M A CS II + - + - - - + + - - ART 100 124/80 39 + - - - + + - - - - - - 10.4 34.9 4400 50 39 4 4 2 2.2 28 NNA - 39 270 22 Mahadeva 3602 35 M A CS II + - + - - + - - - - ART 70 130/70 39 + - - + - - - - - - - - 10.1 35 2600 74 16 2 4 1 2.1 50 NNA - 162 1725 23 Chandregowda 1730 30 M A CS II + - + - - + - - - - - 66 136/80 39 + - - - + + + - - - - - 11.6 11300 3400 50 39 5 6 0 2.4 40 NHA - 268 960 24 Basavaraju 521823 35 M A CS II + - + - - - - - - - ART 76 140/80 39 + - - + + - - - S - - - 5.7 38.3 3800 74 11 2 3 0 0.9 70 NNA - 129 415 25 Satish 2542 30 M A CS II - - + - + + - + - - ART 70 119/70 39 + - - + + + - - Pa - - - 4.6 36 2600 44 54 1 1 0 0.8 18 NNA - 18 340 Sl. No. Name IP/ART No. Age Sex Occupation

Diagnosis Fatigue Fever Weight loss Jaundice Dyspnoea Anorexia Cough Diarrhoea Palpitation Miscellaneous Associated illness Medications Pulse/mm Bp Temperature Pallor Clubbing Cyanosis Emaciation Oral thrush Adenopathy Edema Petechiae parpura CVS RS PA

CNS Hb% Haematocrit Total count Neutral count (%) Lymphocyte count (%) Monocytes (%) Eosinophils (%) Basophytes (%) Platelet count ESR Peripheral smear Bone marrow study CD4 CD8 26 Raghu 59455 31 M A CSI - - - - + - - - - - - N 90 130/80 39 - - - - - - - - - - - - 9.4 38.4 5800 59 40 0 1 0 1.6 50 NNB - 266 961 27 Shivanna 476523 47 M A CS II - - - - - + - - - - N 86 136/80 39 - - - - + + + - - - - - 10.2 44 6600 66 18 5 9 1.6 2.1 14 NNA - 164 421 28 Jayamma 24 F PTB - - - - - + + + - - - - N 90 120/80 40 - - - - - - - - - RUL - - 8.4 38.8 3200 74 12 2 2 0 1.6 9 NNA - 30 365

29 Mahadeva 593577 30 M A CS II - - - - - - - + - - N 98 110/70 39 - - - - - - - - - - - - 9.1 39 8700 66 40 1 3 0 3.2 23 NHA - 240 740 30 Lakshmi 593578 26 F C CS II - - - - + + - - - - N 80 106/80 39 - - - + + + - - - - - - 10.4 44 9200 57 36 2 5 0 1.8 16 NNA - 76 666 31 Raju 562153 28 M C CS II - - - - - - - - - - - N 102 110/70 39 - - - - - - - - - - - - 11 43.6 7600 68 28 1 2 1 2.5 18 NNA - 146 720 32 Krishnegowda 552718 40 M C CS II - - - - + + + - - - - N 110 124/86 39 - - - - + + + - - - - - 10.6 41.6 3400 56 18 2 3 1 1.9 14 NNA - 38 56 33 Prabhamani 2320 35 F Hw CS II - - - - - - - - - - N 102 130/84 39 - - - - - - - - - - - - 10.8 44.2 6200 50 40 4 5 1 1.6 22 NHA - 54 886 34 Madegowda 2763 35 M A PTB - - - - - - + + D - - N 100 150/90 39 - - - + + + - - - RLC - - 11.6 43.6 7800 58 34 4 3 1 1.7 20 NHA - 24.8 380 35 Puttraju 595582 40 M A CS II - - - - + + - + - - N 100 140/60 39 - - - - - - - - - - - - 12.4 44.2 6800 66 30 1 2 1 3.2 14 NHA - 248 1060 36 Prmegowda 595312 42 M A Puo - - - - - - - - - - N 80 180/100 39 - - - - + + - - - - - - 12 44 3650 57 17 2 4 0 2.4 12 NNA - 125 660 37 Shivu 596166 31 M A PTB - - - - + + - + - - - N 86 110/70 39 - - - + - - - - - RUF - - 10.4 43.2 3900 66 14 0 0 0 3.2 7 NHA - 324 1528

38 Anand 595560 30 M T CS II - - - - - - - - - - ART 90 110/70 39 - - - - + + - - - - - - 9.4 39.8 6700 60 40 0 0 0 1.9 4 NNA - 35 79 39 Prakesh 2451 23 M A CS III - - - - - - - - Sl - ART 100 120/70 39 - + - - + + - - - - 9.8 39 3850 60 10 0 0 0 0.9 15 NHA - 14 315 40 Raheem 51 39 M A CS II - - - - + + - - - - - N 102 114/80 39 - - - - + + - - - - - - 10.3 43.4 7900 60 40 0 0 0 1.9 6 NHA - 120 660 41 Kumar 594441 35 M A CS II - - - - - - - + + - N 90 128/80 39 - - - + + + + - - - - - 11.6 44 8700 75 20 2 3 0 3.7 4 NNA - 288 2008 42 Sumithra 470214 24 F Hw CS II - - - - - - - - - - N 100 124/70 39 - - - - - - - - - - - - 12 45.2 9300 58 40 0.8 1 0 1.2 10 NHA - 115 425 43 Nagappa 594037 35 F C CS III - - - - + + - - - - N 96 136/80 39 - - - - + + - - - - - - 12.8 44.6 3200 70 26 2 2 0 1 10 NHA - 27 112 44 Susheela 593547 25 F A CS II - - - - - - - - - - N 98 106/70 39 - - - + - - - - - - - - 7.8 38.4 2900 68 30 4 7 1 0.9 12 NHA - 60 279 45 Venkatesh 585447 32 M A CS I - - - - - - - - - - N 88 110/70 39 - - - - - - - - - - - - 8.4 38.2 3800 69 20 4 5 2 1.1 16 NHA - 40 260 46 Mariyappa 572368 28 M A CS II - - - - + + - - - - ART 100 120/80 39 - - - - + - - - - - - - 4.8 36.2 3900 69 19 5 6 1 1.1 18 NHA - 24 222

47 Ramu 2393 40 M A CS II - - - - + + - - - - ART 70 110/80 39 - - - + - - - - - - - - 10.8 39.4 2950 68 18 5 7.6 1 1.3 14 NNA - 40 6.7 48 Ajith 2804 37 M A CS II - - - - - - - - - - - N 66 116/89 39 - - - - - - - - - - - - 9.9 39 3800 57 41 1 1 0 1.4 8 NNA - 46 710 49 Rajesh 142382 31 M A PTB - - - - - - + - - - - N 76 126/82 39 - - - - + - - - - LUF - - 10.6 43.2 3800 66 20 6 12 1 2.1 10 NNA - 270 700 50 Ravi 1878 35 M A PTB - - - - - - + - - - - N 70 128/80 39 - - - - - - - - - RUF - - 10.4 44.6 2600 64 32 2 2 0 2.4 10 DA NB 236 680 Sl. No. Name IP/ART No. Age Sex Occupation Diagnosis Fatigue Fever Weight loss Jaundice Dyspnoea Anorexia Cough Diarrhoea

Palpitation Miscellaneous Associated illness Medications Pulse/mm Bp Temperature Pallor Clubbing Cyanosis Emaciation Oral thrush Adenopathy Edema Petechiae parpura CVS RS PA CNS Hb% Haematocrit Total count Neutral count (%) Lymphocyte count (%) Monocytes (%) Eosinophils (%)

Basophytes (%) Platelet count ESR Peripheral smear Bone marrow study CD4 CD8 51 Nanjundappa 2800 50 M A Puo Y Y Y N - - + - - - Art 90 120/80 39 - - - - + + - - Sm - - - 5.3 36.8 3600 74 18 2 2 0 0.8 85 PA HP 23.5 24.8 52 Sudha 593003 30 F Hw CS I Y - - N + + + + - - Art 86 116/84 39 - - - - - - - - - - - - 7.8 40.6 3800 82 16 4 6 2 0.9 110 DA NB 32 281 53 Mallesh 3422 20 M C CS II Y + Y N N + + - - - Art 90 120/70 39 - - - + + + - - - - - - 8.6 38.6 3450 84 14 1 1 0 1.9 42 NNA - 150 308 54 Panner 3759 12 M C CS II Y + Y N N - - - - - Art 98 120/79 39 - - - - - - - - - - - - 9 39.6 3900 76 12 1 1 0 2.2 16 NNA - 109 420 55 Savithramma 599852 35 F C CS II Y + Y N + + + - - - - N 80 120/79 39 - - - - + + - - - - - - 12.2 46.4 5300 73 20 2 4 1 3.4 22 NNA - 364 532 56 Ningaraja 599853 42 M A MTB Y + Y - N + + + - - - N 102 110/80 39 - + - + - - - - - - - - 11.6 43.2 3600 72 16 2 2 0 3.6 16 NNA - 281 2000

57 Basavaraja 597631 30 M T CS II Y - - N - + + - - - N 110 144/70 39 - - - + + + + - - - - - 6.4 36.5 7000 54 43 1 1 1 0.8 50 PA HP 21 560 58 Puttalingamma 586741 38 F Hw CS II Y Y Y N + + + - - - - N 102 130/80 39 - - - - - - - - - - - 8.8 38 8600 56 38 2 4 0 1.9 34 NNA - 1.51 550 59 Shankri 601971 21 F Hw CS I Y Y Y N - - - - - - N 100 104/70 39 - - - + + + - - - - Sp - 9 39 7800 60 34 2 3 1 1.8 22 NNA - 107 1183 60 Jayaram 601972 26 M A CS III - Y - N + + + - - - N 100 110/74 39 - - - - - - - - - - - - 6.3 36.6 6600 58 40 0.5 1 0 1.7 18 NNA - 24.4 383 61 Raju Javaraih 2207 36 M A Puo Y Y Y N - - - - - HTN Art 80 160/94 41 - - - - + + - - - - - - 8.8 39.6 10500 59 33 2.6 3 2 1.8 7 NNA - 29.3 217 62 Ravi 1772 34 M A Ptb Y Y Y N + + + + + - - N 86 120/80 39 - - - + + + - - - - - - 6.2 37 3800 66 11 2 1 0 0.7 55 DA HC 8.62 304 63 Ramesh 601167 37 M A CS II Y - - N - - - - - - N 90 114/66 39 - - - - - - - - - - - - 8.8 43 9000 68 29 1 2 0 1.9 10 NNA - 114 822 64 Prasanna 593615 55 M A CS II Y Y Y N - - - - - - N 100 120/80 39 - - - - - - - -- - - - - 9.6 40.2 3600 59 32 3 4 3 1 18 NNA - 220 770 65 Papanna 600355 35 M A CS II - Y Y N + + + - - - N 102 130/80 39 - - - + + + + - - - - - 10.6 43.5 3300 69 27 2 2 0 2.1 22 NNA - 115 670

66 Chinnaswamy 2045 38 M A CS III Y Y Y N - - - - - - ART 90 120/80 39 - + - - + + - - - - - - 13 45 10300 67 18 3 4 2 1.4 16 NHA - 243 1056 67 Mutturaj Swamy 3761 26 M CS II Y - - N N - - - - - - N 100 110/80 39 - - - - - - - - - - - - 13.4 46 7800 60 34 2 3 1 0.9 40 NNA - 41 244 68 Prabhuswamy 1493 30 M A PTB Y Y Y N + + + - - - - N 96 120/80 39 - - - + - - - - - RLLC - 13.6 46.2 9000 58 38 2 2 0 2.4 28 NNA - 125 665 69 Umesh 2883 31 M A PUO - Y Y N - - - - - - - N 98 110/86 39 - - - - + + - - - - - - 11.6 41.5 3650 54 11 2 3 0 1.8 22 NNA - 31 75 70 Devraj 3744 25 M C CS II Y Y Y N + + + + - - N 88 120/80 39 - - - + + + - - - - - - 10.2 40 8000 64 33 1 2 0 1.8 18 NNA - 97 945 71 Honnappa 3792 32 M A CS I Y - - - - - - - - - ART 100 126/80 40 - - - + - - - - - - - - 9.8 41 9600 64 31 2 3 0 1.6 12 NNA - 50 660 72 Girigowda - 36 M A CS IV Y Y Y N - - - - - - ART 70 130/80 39 - + - - - - - - - - - - 4.4 36 3400 57 40 0.8 2 0 1.8 18 AMHA - 27 112 73 Ravi 3778 31 M A CS I Y Y Y N + + + - - - ART 66 136/84 39 - - - + - - - - - - - - 14.6 45 2900 59 40 0 1 0 2.4 20 NHA - 126 594 74 Bhavani 606745 29 F Hw CS I Y - - N - - - + - HTN N 76 140/86 39 - - - - - - - - - - - - 12.4 43 3300 69 19 4 6 2 1.4 14 NHA - 310 1516

75 Some Gowda 604085 42 M A PTB Y Y Y N + - - - - - - ART 70 120/80 39 - - - - - - - - - LUF - 12.1 43.2 3800 64 30 2 3 1 4.1 8 NHA - 140 1363 Sl. No. Name IP/ART No. Age Sex Occupation Diagnosis Fatigue Fever Weight loss Jaundice Dyspnoea Anorexia Cough Diarrhoea Palpitation Miscellaneous Associated illness Medications Pulse/mm Bp Temperature Pallor Clubbing

Cyanosis Emaciation Oral thrush Adenopathy Edema Petechiae parpura CVS RS PA CNS Hb% Haematocrit Total count Neutral count (%) Lymphocyte count (%) Monocytes (%) Eosinophils (%) Basophytes (%) Platelet count ESR Peripheral smear Bone marrow study CD4 CD8

76 Venugopal 3627 35 M A CS III - - - - - - - - Bg - N 90 120/80 39 - - - - - - - - - - - - 8.6 41 2400 42 53 2 3 0 0.9 55 PA NB 34 369 77 Chandrashekar 477193 28 M A CS II - - - - + + + + - - - N 86 110/70 39 - - - - + + + - - - - - 9 42 6400 72 19 3 4 2 1.1 4 NNA HC 41.5 54.5 78 Mahaveer 2546 31 M A CS II - - - - + + + + - - N 90 14/70 39 - - - - - - - - - - - - 7.8 38.4 7600 74 20 1.2 3 2 1.3 30 NNA - 45.6 641 79 Narayanappa 588119 60 M A PUO - - - - - - - - - - N 98 124/80 39 - - - + + - - - - - - - 13.4 41 7200 58 36 2 3 1 3.6 15 NNA - 884 706 80 Natraj 3748 27 M A CS II - - - - - - - - - - - ART 80 130/80 40 - - - - - + - - - - 10.1 42.4 8600 60 32 4 4 0 1.2 16 NHA - 28.2 201 81 Akram 3787 30 M A PTB - - - - + + + - - - ART 102 140/84 39 - - - - - + + - - TBL - - 9.6 40 7600 66 30 1 2 1 0.9 40 NNA NB 26 503 82 Madalambike 1354 32 M A CS II - - - - - - - - - - ART 110 130/60 39 - - - + - - - - - - -- - 9.9 39 3400 65 19 2 3 1 1.8 16 NNA NB 34 1094 83 Beerappa 61670 30 M A PTB - - - - + + +- - - - N 102 116/80 39 - - - - - - - - MTB - - 10.2 40.2 5800 57 37 2 3 1 1.7 8 NNA - 32 48 84 Shivalinga 179679 29 M A CS II - - - - - - - - - - N 100 104/70 39 - - - + + + - - - - - - 8.8 38 9200 55 38 4 6 2 2.2 12 NNA - 130 415

85 Nethra 88022 25 F Hw CS II - - - - + + + - - - N 100 110/70 39 - + - - - - - - - - - - 7.8 37.4 8600 58 37 1.6 3 1 1.9 18 NHA - 43.2 420 86 Ganga 524835 19 F Hw CS II - - - - - - - - - - N 80 120/80 39 - - - + + - - - - - - - 8.6 39.2 7800 66 38 2 3 1 2.4 7 NHA - 164 1721 87 Pathima 362973 26 F C CS II - - - - + + + + - - ART 86 110/70 39 - - - - - - - - - - - - 10.4 44 6550 57 39 2 2 0 1.9 8 NHA - 44 755 88 T. Panneelselvam 599938 38 M A CS II - - - - - - - - - - ART 90 114/68 39 - - - - + + - - - - - - 11.4 45 3250 68 18 4 4 2 2.1 14 NHA - 47.9 123 89 Preema 599939 30 F Hw CS II - - - - + + + - - - ART 100 120/80 39 - - - - - - - - - - - - 8.6 39.4 10500 66 28 2 2 2 2.2 14 NHA - 80 365 90 Nanjegowda 617958 37 M C PTB - - - + - - + - - - ART 102 110/70 39 - - - + + - + - - - - - 6.9 38.2 4800 53 39 3 4 1 2.5 18 NNA - 220 1884 91 Maharaj 618235 29 M C CS II - - - - + + + - - - ART 90 120/80 39 - - - - - - - - - PL - - 7.8 36.2 3850 55 11 2 2 0 4.3 7 NHA - 164 1721 92 Nagamma 612025 45 F C CS II - - - - - - - + + - ART 100 110/80 39 - - - - - - - - - - - - 10.1 44 6500 64 32 1.4 2 2 3.4 12 NHA - 430 721 93 Someshakar 614554 26 M A CS II - - - - + + - - - - N 96 124/80 39 - - - + + + - - - - - - 9.8 43 7800 66 30 1.8 2 1 3.6 14 NNA - 140 722

94 Ningaiah 618119 50 M A CS II - - - - + + - - - - N 98 116/80 39 - - - - - - - - - - - - 8.2 40 8200 69 24 3 4 0 1.8 32 NNA - 40 660 95 Venkatachala 470469 52 M A CS I - - - - + - - - - - N 88 120/80 39 - - - - - - - - - - - - 9.9 41.4 8450 56 39 1.6 2 2 2.4 18 NHA - 214 740 96 Mahesh 618004 36 M A CS II - - - - + + + - - - N 100 116/84 39 + - - + + + - - - - - - 10.4 44.1 8600 66 30 2 2 0 2.5 22 NHA - 156 628 97 Indresh Kumar 253038 36 M A PTB - - - - + + - - - - ART 70 120/80 39 - - - - - - - - - LUF - 8.6 39 7800 56 40 2 2 0 1.9 16 NHA - 180 704 98 Ravishetty 598460 41 M A CS II - - - - + + + - - - N 66 124/86 39 - - - + + + - - - - - - 7.9 37.4 3250 57 11 0.2 1.8 0 4.5 8 NHA - 146 1860 99 K.M.Shivarudrappa 534302 55 M A CS II - - - + - - - - - - N 76 120/80 39 - - - - - - - - - -- - - 9.8 40.6 9700 69 19 4 7 1 3.6 12 NHA - 826 726 100 Lingaraju 616623 49 M A CS III - - - - - + + - - - N 70 124/68 39 - - - - - - - - -- - - - 8.3 39.4 2900 48 48 1.6 2 1 2.4 10 NHA - 48 1086 CD4/CD8 0.08 0.14 0.3 0.1 0.18

0.17 0.2 0.2 0.03 0.18 0.15 0.14 0.19 0.14 0.05 0.1 0.1 0.1 1.25 0.26 0.22 0.1 0.28 0.31 0.09 CD4/CD8 0.28 0.1 0.22 0.6 0.1 0.19

0.2 0.07 0.06 0.24 0.18 0.2 0.4 0.03 0.2 0.14 0.26 0.24 0.22 0.18 0.13 0.1 0.2 0.21 0.17 CD4/CD8 0.09 0.22 0.99 0.26 0.68 0.14 0.04

0.27 0.09 0.06 0.13 0.03 0.14 0.29 0.17 0.23 0.17 0.19 0.4 0.1 0.08 0.24 0.21 0.2 0.1 CD4/CD8 0.09 0.08 0.07 1.25 0.14 0.05 0.05 0.27

70.3 0.1 0.1 0.15 0.63 0.22 0.12 0.1 0.6 0.19 0.1 0.28 0.24 0.25 0.08 1.23 0.05