Natural History of HIV Disease

Updated October, 2010

 

Brian Montague DO MS MPH, Timothy Flanigan MD

Previous Author (2003): Susan Swindells, MBBS

 

               HIV disease is characterized by progressive depletion of CD4 lymphocytes with subsequent compromise of the body’s immune function. The majority of data regarding the natural history of HIV is derived from studies of HIV-1 subtype B in North America and Western Europe from the pre-HAART era. The rate of decline in CD4 count varies from individual to individual, with the median time from infection to significant illness (AIDS) being between 8-10 years in most studies (40).  Data is much more limited regarding other subtypes, which are more prevalent globally, with mixed reports regarding difference in rates of disease progression by subtype (20, 35). There is no evidence of significant differences in response to treatment by subtype and subtype testing is not recommended as part of routine clinical evaluation. Significant individual variability exists in the rate of CD4 decline and the development of HIV associated morbidity and opportunistic infections, only a portion of which is explained by known prognostic factors.

               Traditionally, the natural history of HIV disease has been described in three phases: acute infection, asymptomatic phase, and symptomatic disease. The diagnosis of AIDS (Acquired Immune Deficiency Syndrome) was given when the CD4 count dropped below 200. Increasingly, however, it has become appreciated that even during what was previously considered an asymptomatic phase of disease, patients are vulnerable to a variety of infections, particularly tuberculosis (TB) and other bacterial infections. HIV at all stages can cause direct tissue inflammation and injury attributable to proliferating virus, accelerated progression of comorbid infections such as viral hepatitis, and increased susceptibility to other infections such as reactivation tuberculosis disease. Prior to the advent of Highly Active Antiretroviral Therapy (HAART), the median survival from the time of AIDS diagnosis was estimated to be approximately 20 months (25). With the advent of Highly Active Antiretroviral Therapy (HAART), short-term AIDS related mortality has become the exception and most patients can expect full effective immune reconstitution.

Acute Retroviral Syndrome

               Following infection, patients experience an acute and large elevation in viral load often reaching levels greater than a million copies per ml. This viremia is frequently accompanied by a significant drop in CD4 count and may be associated with symptoms of fever, lymphadenopathy, myalgia, arthralgia, pharyngitis, and at times a maculopapular rash (14). Other less frequent symptoms include, headache, oral ulcers, nausea, anorexia, and gastrointestinal upset. In published series, upon specific questioning between 50 and 90% of patients recall some degree of symptoms at the time of infection (17).  Because these symptoms are non-specific and may be mild, patients may not report any awareness of an acute viral syndrome. The time from infection to the development of symptoms is typically in the range of 2-4 weeks. Specific and rapid depletion of CD4 cells from the gastrointestinal tract has also been described during this acute phase of HIV infection (23).  Symptoms may last for up to 3 weeks and wane as the the body’s immune response is able to reduce the level of viremia. IgM antibodies can be demonstrated in the first few days after the time of infection (32).  IgG becomes detectable within an average of 2-3 weeks post infection. The assessment of IgG by ELISA or other assays is the basis of most commercially used assays for screening.

               After an average of 2-3 months, cellular immune responses contribute to a greater than 1000 fold drop in viral load with associated CD4 recovery (13). A new viral set point and peak CD4 count are typically achieved by six months after infection. The subsequent rate of progression of disease is influenced by both the peak CD4 count and the nadir viral load at the time of recovery, however significant variability exists between individuals with regard to the rate of disease progression (24, 30) Over the subsequent course of the infection, prior to treatment, the viral load progressively increases and the CD4 proportionally declines as shown in Figure 1. Because symptoms are uncommon until the CD4 count has declined significantly below 500, in the absence of active screening and case finding activities, patients are often not diagnosed until significant CD4 decline has already occurred. Efforts towards screening and early diagnosis are critical, therefore, both to minimize morbidity associated with the disease and to maximize each individual’s response to antiretroviral therapy.

Progressive Manifestations of Disease

               The manifestations of HIV disease increase as the CD4 count declines as described in Table 1 (4). In uninfected individuals, the CD4 count typically is greater than 750 and may be greater than 1000. In patients with HIV at CD4 counts above 500, patients may have an increased rate of herpes zoster reactivations. When the CD4 count declines to in the range of 200-500, patients may experience increased rates of oropharyngeal candidiasis, increased susceptibility to bacterial infections,TB, lymphomas, and Kaposi’s sarcoma. When the CD4 count declines less than 200, patients become susceptible to a wide array of opportunistic infections as well as disseminated forms of AIDS associated malignancies. Rates of reactivation tuberculosis disease are higher in HIV patients of any CD4 count, however extrapulmonary disease has been shown to be significantly more common at lower CD4 counts. Worldwide, tuberculosis diseases is one of the most important determinants of both morbidity and mortality amongst patients with HIV.

               Other manifestations of HIV disease are less clearly tied to the CD4 progression. High rates of viral replication, independent of CD4 count, through endothelial activation and progressive atherosclerosis appears to increase the risk of cardiovascular disease (19).  Dilated cardiomyopathies, though more common in those with lower CD4 count may occur even in patients with CD4 counts greater than 400. This variability may reflect the multiple proposed underlying causes including HIV virus triggered apoptosis of cardiac myocytes, viral myocarditis, and drug induced myocardial toxicity for those on antiretroviral treatment (2, 19).  HIV associated nephropathy is most commonly diagnosed in patients with low CD4 counts, however, studies suggest that kidney injury may occur earlier and accelerate as the CD4 count declines (5, 26).  HIV associated peripheral neuropathy and dementia are not typically seen until the CD4 count drops below 200 (3, 9, 33).  The toxic effect of antiretroviral medications (most significantly stavudine and didanosine) is thought to be an important cofactor in the development of HIV associated peripheral neuropathies, and may be a more important predictor of the development of neuropathies than the CD4 count itself.

Clinical Staging of HIV Disease

               Due to the inconsistent availability of CD4 counts in many resource limited settings, a system of clinical staging has been established by the World Health Association for the purposes of guiding initiation of antiretroviral therapy, pneumocystis prophylaxis and other management (Table 2). Because many of the associated symptoms are nonspecific, this staging presupposes an existing diagnosis of HIV infection which can only be made in the context of a positive HIV antibody test. Therapy is generally indicated for patients in clinical stage III or IV. With effective antiretroviral therapy, patients with advanced disease may be restaged based on their clinical improvement (Table 2).

               In their 1993 surveillance case definitions, the CDC maintained a similar system of clinical staging based on the combination of CD4 count and various symptoms and conditions suggestive of progressive immunodeficiency (6). In 2008, revised guidelines were issued establishing staging primarily based on quantification of the level of immunodeficiency based on CD4 count and CD4 percentage as shown in Table 3 (7). Clinical evidence of an AIDS-defining condition was retained as sufficient evidence for stage 3 disease (AIDS). It is important to note that, unlike the WHO staging system, the CDC guidelines were intended as supports for public health surveillance and were not intended to be used as guides for decisions regarding antiretroviral treatment or other aspects of HIV management. For clinical purposes, the CDC recommends staging only based on CD4 count and/or CD4 percentage in accordance with current treatment guidelines.

Guideline:  Aberg JA, et al.  Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America.  Clin Infect Dis 2009;49:651-681. 

HIV-1 vs. HIV-2

               Less data is available regarding the natural history of HIV-2 (10).  HIV-2 typically progresses more slowly, with stable counts over extended durations. Viral loads in patients with HIV-2 are similarly lower. The spectrum of opportunistic infections in HIV-2, as in HIV-1, is determined principally by CD4 count. In one survey from a West African clinic comparing matched patients with HIV-1 and HIV-2, Kaposi’s Sarcoma was significantly less common in patients with HIV-2 disease (22). As the prevalence of HIV-1 rises in areas with endemic HIV-2, mixed infections with HIV-1 and HIV-2 have been described. Though the natural history of these dual infections has not been well described, there is some indication that HIV-1 may dominate and at advance stages with minimal or no detectable activity of the HIV-2 virus (31).

Impact of Treatment on Natural History of Disease

               After commencing antiretroviral treatment, patients experience an initial rapid drop in viral load. In the absence of antiretroviral resistance, by 3 months on HAART patients should have achieved reductions in viral load below the limits of detection by most assays. In some patients, despite adequate antiretroviral therapy and susceptible virus, serial viral load assays demonstrate episodes of low-level viremia, typically less than 400 copies per ml. These episodes probably represent transient mobilization of virus from protected sites and other cell lines. Though the risk of development of antiretroviral resistance, is thought to be low, resistant mutants have been demonstrated in some studies (28, 34, 37).  CD4 recovery on treatment typically begins at 1-2 months and counts may continue to rise for many years. Despite repopulation of circulating CD4 cells, CD4 depletion in the gastrointestinal mucosa may be irreversible (23). The extent of immune recovery has been shown to vary based on the CD4 count at the time of initiation of treatment with a median rise per patient in some series as low as 200 (18, 26) The long-term prognostic significance of the plateau in CD4 count has not been well established but some series have shown increased rates of disease progression and both AIDS and non-AIDS mortality (12).  Early diagnosis and treatment is the most important determinant of positive outcomes for patients with HIV disease.

               A portion of patients with markedly suppressed immune function (typically CD4 <100 cells /mm3) prior to the initiation of HAART may experience an inflammatory syndrome known as IRIS (Immune Reconstitution Inflammatory Syndrome) with the recovery of their immune function. This is thought to represent the development of an immune response to previously tolerated infections or exogenous antigens. Though many opportunistic infections may be associated with IRIS, these events are particularly frequent in association with underlying mycobacterial infections such as tuberculosis, cryptococcosis and other viral infections such as hepatitis B (11). Though not typically life threatening, IRIS events may have significant morbidity depending on the foci of symptoms. Particularly with CNS IRIS events, adjunctive corticosteroids have been used as treatment where symptoms are severe in an attempt to limit the associated morbidity (39).

               Virologic suppression and CD4 cell recovery may reduce or reverse the progression of many complications of HIV disease. For patients with HIV associated malignancies such as primary CNS lymphoma or Kaposi’s sarcoma, antiretroviral therapy is an important adjunct to chemotherapy and significantly improves the prognosis with treatment. HAART has been shown to decrease the progression of renal glomerular injury associated with HIV disease. Reduction in viral replication has the potential to reduce development of cardiovascular disease through reduced endothelial activation and normalization of lipid parameters. Some opportunistic infections such as progressive multifocal leukencephalopathy (PML) and cryptosporidiosis only respond to antiretroviral therapy. HIV associated neuropathy and dementias both may respond to effective antiretroviral therapy, however, the full extent of the recovery may vary based on the extent of the underlying injury at the time treatment is initiated (9, 21).  Because certain antiretroviral agents have been implicated in the pathogenesis of HIV associated peripheral neuropathies, use of alternative, less neurotoxic agents, is critical to preventing further nerve injury.

               With extended use, HAART has also been associated with an increase in risk of cardiovascular disease through changes in lipid profiles and the development of glucose intolerance. With strict attention to risk factor modification including smoking cessation, dietary changes and medication therapy as indicated for glucose intolerance and hyperlipidemia, this increase in risk may be mitigated.

Long-Term Nonprogressors and Elite Controllers

               In some individuals the rate of HIV progression is much slower (29).  Long-term non-progressors typically have low viral loads (less than 10,000). CD4 counts in this group may remain greater than 350 for periods in excess of 20 years. A small subgroup, known as elite controllers, may have no detectable viremia in the absence of antiretroviral therapy. The full natural history of disease for these patients is not known. In some series, patients demonstrate a decline in CD4 count over periods of many years, despite the continued absence of viremia (16) The extent to which this decline in CD4 count portends developing immune compromise and the appropriate threshold for consideration of antiretroviral therapy remain active areas of investigation.

Trends in Mortality Related to HIV

               Studies of mortality amongst patients with HIV in the era of Highly Active Antiretroviral Therapy (HAART) derived principally from the United States and western Europe, demonstrate a marked reduction in the mortality associated with opportunistic infections (15).  Significant variability exists between populations, but liver disease, cardiovascular disease and non AIDS defining malignancies are all emerging as important determinants of survival in patients with HIV. For liver disease related mortality, this reflects the high rates of coinfection with hepatitis B and/or hepatitis C in various populations around the world, both of whom show accelerated progression in the presence of HIV. For those without significant liver disease, the overall life expectancy amongst patients with HIV on HAART in some cohorts approaches that of matched cohorts without HIV infection (9, 27).
Zhang F, et al. Five-Year Outcomes of the China National Free Antiretroviral Treatment Program. Ann Intern Med. 2009 Aug 18;151:241-51, W-52.
 

Natural History of HIV in Children

               Less data is available regarding the natural history of HIV in infants and children. Untreated, the mortality for infants infected with HIV is extremely high with a median survival of 75-90 months (38).  In many resource limited settings, access to testing and antiretroviral therapy is limited for infected children. Very early initiation of HAART in HIV infected children provides the most benefit. Surveillance for HIV associated outcomes may also be inadequate. With adequate access to antiretroviral therapy, life expectancy amongst those on adequate HAART has increased similar to in the adult population. It remains to be seen whether long-term survival for these cohorts will be comparable to that of adults started on therapy.

 

FIGURE AND TABLES

Figure 1:  Natural History of HIV-1 Disease In the Absence of Treatment

Table 1:  Relationship between CD4 and Complications of HIV Disease, Reproduced From Cecil’s Essentials of Medicine, 7th Edition (4)

Table 2:  Revised WHO Clinical Staging of HIV/AIDS for Adults and Adolescents (1)

Table 3:  Surveillance Case Definition for Human Immunodeficiency Virus (HIV) Infection Among Adults and Adolescents (aged >13 years) — United States, 2008 (7)

 

REFERENCES

1. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. WHO [ 2009 Available from: URL:http://www.who.int/hiv/pub/guidelines/hivstaging/en/index.html

2. Barbaro G, Di Lorenzo G, Grisorio B, Gruppo Italiano Per Lo Studio Ccardiologico Dei Pazienti Affetti Da AIDS. Incidence of Dilated Cardiomyopathy and Detection of HIV in Myocardeial Cells of HIV-Positive Patients. NEJM 1998; 16(339):1094-1099. [PubMed]

3.  Bhaskaran K, Mussini C, Antinori A, Walker AS, Dorrucci M, Sabin C et al. Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Annals of Neurology 2008;63:213-221. [PubMed]

4.  Carpenter C, Beckwith C, Rodriguez B, Leventhal JS. Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome. In: Andreoli T, Carpenter C, Griggs R, Benjamin I, editors. Cecil Essentials of Medicine. 7th ed. Philadelphia: Saunders/Elsevier; 2009. 989-1008. [PubMed]

5.  Cavalcante MA, Coelho SN, Lacerda HR. Prevalence of persistent proteinuria in stable HIV/AIDS patients and its association with HIV nephropathy. Brazilian Journal of Infectious Diseases 2007;11:456-461. [PubMed] 

6. CDC. Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1992;41(RR-17). [PubMed] 

7.  CDC. Revised Surveillance Case Definitions for HIV Infection Among Adults, Adolescents, and Children Aged <18 Months and for HIV Infection and AIDS Among Children Aged 18 Months to <13 Years — United States, 2008. MMWR 2008;57(RR-10):1-12. [PubMed] 

8. Cooper DA. Life and death in the cART era.[comment]. Lancet 2008; 372(9635):266-267.  [PubMed] 

9. Cornblath DR, Hoke A. Recent advances in HIV neuropathy. [Review] [28 refs]. Current Opinion in Neurology 2006;19:446-450. [PubMed]

10. de Silva TI, Cotten M, Rowland-Jones SL. HIV-2: the forgotten AIDS virus. Trends in Microbiology 2008;16:588-595. [PubMed] 

11. French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. [Review] [67 refs]. Clinical Infectious Diseases 2009;48:101-107.  [PubMed] 

12.  Gazzola L, Tincati C, Bellistrì GM, Monforte A, Marchetti G. HIV/AIDS: The Absence of CD4+ T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy: Clinical Risk, Immunological Gaps, and Therapeutic Options. Clinical Infectious Diseases 2009;48:328-337.  [PubMed]

13.  Gray C, Walker B. The Immune Response to HIV. In: Volberding P, Sande M, Lange J, Greene W, editors. Global HIV/AIDS Medicine. 1 ed. China: Saunders/Elsevier; 2009. 39-49. [PubMed]

14. Hicks CB, Gay C, Ferrari G. Acute HIV infection: the impact of anti-retroviral treatment on cellular immune responses. [Review] [59 refs]. Clinical & Experimental Immunology 2007;149:211-216. [PubMed] 

15.  Hooshyar D, Hanson DL, Wolfe M, Selik RM, Buskin SE, McNaghten AD. Trends in perimortal conditions and mortality rates among HIV-infected patients. AIDS 2007;21:2093-2100.  [PubMed] 

16. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. Journal of Infectious Diseases 2008;197:126-133.  [PubMed] 

17. Kelleher A, Cooper D. Acute HIV Infection. In: Volberding P, Sande M, Lange J, Greene W, editors. Global HIV/AIDS Medicine. 1 ed. China: Saunders/Elsevier; 2009. 63-74. [PubMed] 

18. Kelley C, Kitchen C, Hunt P, Rodriguez B, Hecht F, Kitahata M et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment.  Clinical Infectious Diseases 2009; 48(6):787-794. [PubMed]

19.  Khunnawat C, Mukerji S, Havlichek Jr D, Touma R, Abela G. Cardiovascular Manifestations in Human Immunodeficiency Virus-Infected Patients. American Journal of Cardiology 2008; 102:635-642. [PubMed] 

20.  Kiwanuka N, Laeyendecker O, Robb M, Kigozi G, Arroyo M, McCutchan F et al. Effect of human immunodeficiency virus Type 1 (HIV-1) subtype on disease progression in persons from Rakai, Uganda, with incident HIV-1 infection.[see comment]. Journal of Infectious Diseases 2008;197:707-713. [PubMed] 

21. Lichtenstein KA, Armon C, Baron A, Moorman AC, Wood KC, Holmberg SD et al. Modification of the incidence of drug-associated symmetrical peripheral neuropathy by host and disease factors in the HIV outpatient study cohort. Clinical Infectious Diseases 2005;40:148-157.  [PubMed] 

22.  Martinez-Steele E, Awasana AA, Corrah T, Sabally S, van der Sande M, Jaye A et al. Is HIV-2- induced AIDS different from HIV-1-associated AIDS? Data from a West African clinic. [Article]. AIDS 2007;21:317-324. [PubMed]

23. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C et al. Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract. J Exp Med 2004; 200(6):761-770. [PubMed]

24. Mellors JW, Munoz A, Giorgi J, Margolick J, Tassoni C, Gupta P et al. Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection. Annals of Internal Medicine 1997; 126(12):983-985. [PubMed] 

25.  Mocroft A, Youle M, Morcinek J, Sabin C, Phillips A, Johnson M. Survival After Diagnosis of AIDS: a Prospective Observational Study of 2625 Patients. BMJ 1997;314:409-413. [PubMed]

26. Moore R, Keruly J. CD4+ Cell Count 6 Years after Commencement of Highly Active Antiretroviral Therapy in Persons with Sustained Virologic Suppression. Clinical Infectious Diseases 2007;44:441-446. [PubMed] 

27. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.[see comment]. Lancet 2008;372(9635):293-299.  [PubMed]

28. Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proceedings of the National Academy of Sciences of the United States of America 2008; 105(10):3879-3884. [PubMed]

29. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, Rathod A et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. Journal of Infectious Diseases 2008; 197(4):563-571.  [PubMed] 

30. Rodriguez B, Sethi A, Cheruvu V, Mackay W, Bosch R, Kitahata M et al. Predictive Value of Plasma HIV RNA Level on Rate of CD4 T-Cell Decline in Untreated HIV Infection. JAMA 2006; 296(12):1498-1506. [PubMed] 

31. Sarr AD, Hamel DJ, Thior I, Kokkotou E, Sankale JL, Marlink RG et al. HIV-1 and HIV-2 dual infection: lack of HIV-2 provirus correlates with low CD4+ lymphocyte counts. AIDS 1998; 12(2):131-137. [PubMed] 

32. Shepherd J, Laeyendecker O, Quinn TC. Laboratory Testing for HIV Infection. In: Volberding P, Sande M, Lange J, Greene W, editors. Global HIV/AIDS Medicine. 1ST ed. China: Saunders/Elsevier; 2008. 101-110. [PubMed]

33. Simpson DM, Kitch D, Evans SR, McArthur JC, Asmuth DM, Cohen B et al. HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology 2006;66:1679-1687. [PubMed] 

34. Sirvent JL, Socas MM, Calzadilla CH, Lirola AM, Valls MR. Utility of interrupting antiretroviral treatment before HIV drug resistance testing in patients with persistently detectable low-level viremia. Journal of Acquired Immune Deficiency Syndromes: JAIDS 2005; 40(1):111-113. [PubMed]

35. Spira S, Wainberg MA, Loemba H, Turner D, Brenner BG. Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance. J Antimicrob Chemother 2003;51:229-240. [PubMed] 

36. Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney International 2004;66:1145-1152. [PubMed] 

37. Tobin NH, Learn GH, Holte SE, Wang Y, Melvin AJ, McKernan JL et al. Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus. Journal of Virology 2005; 79(15):9625-9634. [PubMed] 

38. Touloumi G, Hatzakis A. Natural history of HIV-1 infection. [Review] [152 refs]. Clinics in Dermatology 2000;18:389-399. [PubMed]

39. Venkataramana A, Pardo C, McArthur JC, Kerr D, Irani D, Griffin J et al. Immune Reconstitution Inflammatory Syndrome in the CNS of HIV-Infected Patients. Neurology 2006;67:383-388.  [PubMed] 

40. Vergis EN, Mellors JW. Natural history of HIV-1 infection. [Review] [136 refs].  Infect Dis Clin North Am. 2000;14:809-25, v-vi. Review.  [PubMed]