HIV

Current Concepts in HIV Pathogenesis and Treatment

Over the past several years, great strides have been taken in the understanding and treatment of the human immunodeficiency virus. Death rates due to HIV have declined significantly since the introduction of protease inhibitors. Despite the advances in the field, health practitioners are still quite limited in their ability to curb this disease: 40,000 new HIV infections occur every year in the United States. This article will review the new advances in pathogenesis and treatment and discuss the limitations faced in treating the disease.

Human immunodeficiency virus is an RNA virus that targets cells carrying the CD4 antigen. Recently, more details of the life cycle of HIV have been elucidated. After gaining entrance into the body, HIV infection primarily involves the CD4 lymphocytes but also includes macrophages, dendritic cells, microglial cells of the central nervous system, and others. The envelope protein, gp120, uses the CD4 antigen as a receptor for initial attachment. Then a conformational change occurs that requires the interaction of gp120 with a co-receptor (usually the chemokine receptor CCR5). This enables the second envelope protein, gp41, to interact with the cell membrane and allows HIV to gain entrance into the cell.

The RNA of HIV is then copied into double-stranded DNA by the viral enzyme, reverse transcriptase. After the viral DNA is transported to the nucleus and integrated into the host genome, the infected CD4 cell begins producing viral proteins and viral RNA. New viral particles bud off the host cell membrane. The HIV protease enzyme modifies the viral proteins so that the resulting viral particle is a mature, infectious virion.

Each step of the HIV life cycle is being studied as a potential site for antiviral therapy. The current Food and Drug Administration-approved drugs target the reverse transcriptase and protease enzymes. Agents that work at the site of gp41, chemokine receptor blockers and integrase inhibitors, are under investigation.

Acute HIV Infection

After initial exposure and local infection, viremia with HIV is thought to occur within five days.¹ Eighty to 90 percent of individuals with acute HIV infection become symptomatic approximately four weeks after exposure. The symptoms are very nonspecific and flu-like. Patients may exhibit one or more of the following: fever, headache, malaise, sore throat, anorexia, nausea, vomiting, rash, lymphadenopathy, and oral ulcers. Symptoms may last for only a few days to several weeks, but on the average they persist for two weeks.² There is no pathognomonic feature. Many patients seek medical care, but the diagnosis of HIV infection will usually be missed unless a careful history of recent risk behaviors is elicited.

During the symptoms of acute HIV infection, one finds extremely high titers of HIV in the blood. After approximately three months, the viral titers decline and remain at a relatively steady state (Figure 1). This decline is due to the host’s cellular immune system, which exerts partial immunological control over HIV. HIV antibodies are often undetectable during acute HIV infection. In fact, the tests used in screening for HIV infection, the ELISA and Western blot, will often turn positive a few weeks after the symptomatic period. Therefore, if the diagnosis of acute HIV infection is suspected and the antibody screen is negative, it may be necessary to turn to an antigen test (p24 antigen or HIV-RNA testing).

Chronic HIV Infection

After the symptoms of acute HIV infection spontaneously resolve, the patient enters the clinically asymptomatic stage. In the absence of therapy, it takes approximately 10 years before the patient will become symptomatic with AIDS-related infections or cancers. During this asymptomatic period, immune deterioration may be taking place, but because of the great reserve of the immune system, no outward signs occur.

HIV infection results in a rapid turnover of CD4 lymphocytes. The destruction of CD4 cells occurs directly and indirectly (through apoptosis). Over time, the CD4 lymphocyte count decreases, but in early disease the CD4 cell count usually remains normal. This is due to the enormous capacity of the immune system to replace these dying cells. Also, perturbations occur in the proportions of CD4 and CD8 cells (the helper:suppressor ratio). The normal ratio inverts; and as the immune deterioration worsens, this ratio becomes smaller and smaller.

When the absolute CD4 cell count falls to less than 200 cells/ml, the extent of immune deterioration is significant and the likelihood of HIV-related illnesses increase. Although many patients may still be asymptomatic, the Centers for Disease Control and Prevention uses this threshold for the categorization of Acquired Immune Deficiency Syndrome. By definition, any patient with HIV infection and a CD4 count of less than 200 cells/ml is categorized as having AIDS.³

Monitoring of Disease

HIV is an infection of the immune system. Aside from the acute flu-like syndrome during primary HIV infection, there are few other manifestations that occur directly from the virus. Rather, the virus slowly, continuously, and silently erodes the immune system. When the immune deterioration gets to a critical level, symptoms of advanced HIV/AIDS present. Usually these manifestations are not directly caused by HIV but by opportunistic infections or cancers that the immune system can no longer control.

CD4 Lymphocyte Cell Count

The CD4 lymphocyte cell count serves as a marker that gives information about the immune status of the HIV-infected individual. These cells are also termed T4 cells or helper cells. The CD4 cell count decreases as disease progression takes place. The normal range for the CD4 cell count is 750-1,000 cells/ml for adults. A patient with a CD4 count of more than 500 cells/ml is generally considered to have early disease. Counts from 200 to 500 cells/ml could be considered moderate disease. A patient with a count of less than 200 cells/ml would be considered in the advanced stage and meets the CDC definition of having AIDS. Those with CD4 cell counts less than 50 cells/ml are considered to be in the very advanced stage.

The CD4 lymphocyte count is used to monitor the severity of immune suppression and guides the physician as to when to administer certain antibiotic prophylaxis to prevent opportunistic infections. For example, prophylaxis to prevent Pneumocystis carinii pneumonia is instituted when the CD4 count falls to less than 200 cells/ml.

Viral Load

While the CD4 cell count is the window on the immune system, the viral load provides information on the activity of the virus. The viral load test is a quantitative measurement of HIV. In the United States, the most commonly used viral load assay is the polymerase chain reaction, which tests for HIV-1 RNA. This test quantitates the number of copies of free HIV-1 RNA per milliliter of plasma (units equals copies/ml). The upper limit of the current test is 750,000 copies/ml while the lower limit is 50 copies/ml. Below this threshold, the test is not sensitive enough to detect HIV and is reported as "undetectable."

At the time of acute HIV infection, viral load testing shows extremely high viral titers, often more than 750,000 copies/ml. After three months, the viral load falls to a steady state ("set point") and then increases again in advanced infection (Figure 1). The viral set point could range from undetectable to more than 750,000 copies/ml. What determines whether the set point will be low, moderate, or high is unclear at this point. What is clear, however, is that the higher the set point, the faster HIV will progress.

Retrospective studies have documented the clinical utility of viral load testing as a prognostic marker. Using the CD4 cell count along with the viral load measurement makes this prognostic indicator even more powerful. Figure 2 shows how HIV infected patients in the Multicenter AIDS Cohort Study with a CD4 count of less than 200 cells/ml and with the highest viral loads had a 85.5 percent chance of developing AIDS-related illnesses within three years. On the other hand, patients with undetectable viral loads and a CD4 count of greater than 750 cells/ml had less than a 1 percent likelihood of progression.⁴

Anti-Retroviral Therapy
Combination Therapy -- HAART

During the past five years, highly potent anti-retroviral drugs have become available to treat HIV infection. When these drugs are used in combination, they have the capacity of significantly suppressing viral replication. This is evidenced by a marked decline in the viral load and is usually accompanied by an increase in the CD4 lymphocyte cell count. Combination therapy that is capable of significantly decreasing the viral load is termed highly active anti-retroviral therapy (HAART) and is commonly referred to as "cocktail" therapy.

The goal of HAART is to suppress viral replication to the lowest possible level. This would be measured on viral load testing as an "undetectable" result (less than 50 copies/ml). In the best of circumstances, HAART therapy is able to lower viral load to an undetectable level in approximately 80 percent of patients. The likelihood of success is lower in patients who have been on anti-retroviral drugs in the past, have very high initial viral loads, or have advanced disease. The duration that a particular regimen will be effective at keeping the viral load at undetectable varies per patient and can range from a few weeks to more than three years.

An undetectable viral load should not be confused with complete viral suppression or viral eradication. Research studies have shown evidence that the majority of patients with longstanding undetectable viral loads still have viral replication taking place, however the currently available tests are not sensitive enough to measure these low values.⁵ Also, viral load testing measures free virus in the plasma, not cell-associated virus. Since HIV is maintained in cells, if cell-associated viral DNA is measured, HIV can be detected. If therapy is stopped, the viral load rebounds. Additionally, it has been discovered that some of the HIV-infected lymphocytes are in latent stage.⁶ These latently infected cells act as a reservoir for HIV. Even if it were possible to eradicate all free virus and cells that were actively producing HIV, when the latently infected cells would activate (months to years later), they would begin producing new virions.

Three classes of anti-retroviral drugs are approved by the FDA for use against HIV infection: nucleoside analogue reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and the protease inhibitors (Table 1). HAART is usually made up of two nucleoside analogues along with a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. The choices of which combination to use and when to initiate therapy are individually determined with the input of the patient and physician. New data regarding anti-retroviral therapy is continually being generated and recommendations of how to use HAART are often modified. Guidelines on how anti-retroviral therapy should be prescribed have been published by the Department of Health and Human Services and the International AIDS Society.^7,8 These documents are regularly updated and take into consideration recent advances, theoretical concerns, and the yet unanswered questions regarding antivirals.

Resistance to Antivirals

The qualities of an optimal antiviral regimen are that it

* Give potent viral suppression;
* Preserve options for future regimens in case of failure; and
* Be a regimen to which the patient will adhere.

This will usually result in clinical success. If any of these parameters is lacking, virological failure with the development of resistance becomes a concern.

Approximately one mutation occurs every time HIV replicates. On the average, in an untreated asymptomatic patient, HIV is replicating 1 billion to 10 billion times a day. Resistance to antivirals arises by specific mutations occurring in specific genes. Although most random mutations have no effect on the sensitivity of HIV to antiviral drugs, some will. In the presence of antiviral drugs, these mutations will be preferentially selected. The way to minimize or prevent the development of resistance is to maximally suppress HIV replication. If HIV is not replicating, mutations cannot develop and the virus will remain sensitive to the current regimen. If an antiviral regimen allows a significant amount of replication to take place, it is presumed that resistant mutations will inevitably develop. High-level resistance to certain antivirals has been demonstrated in less than two weeks of suboptimal therapy. Therefore, it is imperative that whenever therapy is given for HIV disease, it must be potent.

Adherence

A regimen can only be effective if the patient will take it. Adherence directly influences the degree of viral suppression. One study showed that 81 percent of patients who were taking all (more than 95 percent) of their medication achieved viral load measurements of undetectable. Only 6 percent of patients who were taking 70 percent or less of their prescribed medication reached an undetectable value.⁹

Unfortunately, when poorly adherent patients begin complying with their regimen, many still cannot achieve undetectable viral loads. Resistance develops during the period of intermittent adherence, and reinstitution of the same regimen in full doses cannot overcome this resistance. Therefore, when initiating a patient on an antiviral regimen, it is important for the patient to understand the significance of adherence and accept the responsibility of taking the regimen. If the patient is unable to make this commitment to therapy, it may be better to postpone therapy until he or she is ready. Many advocate the use of a placebo or candy regimen for the first few weeks of therapy so the patient can identify and solve any problems related to dosing before starting the antivirals.

Physicians often underestimate the difficulty of adherence to antivirals. The medications may cause numerous side effects in a patient who was previously asymptomatic; the number of pills ranges from five to 25 per day; some medications must be separated from others; some need to be taken on an empty stomach, some with food; etc.

Cross-Resistance

Even with good adherence, a potent regimen may eventually fail. This is usually due to the development of viral resistance. Therefore, when initially prescribing a regimen, it is important to think one step ahead, to what options are left for the next regimen. Unfortunately, future options can become quite limited because of the existence of a significant amount of cross-resistance. High-level resistance to one agent in the non-nucleoside reverse transcriptase inhibitor group usually results in resistance to all the other non-nucleoside reverse transcriptase inhibitors. Significant cross-resistance also exists among the protease inhibitors. Therefore, to preserve future drug options, people treating HIV use the strategy of "sparing" or excluding one class of drugs when initiating therapy. After the original HAART regimen fails, the new regimen would include an agent from the spared class. The chances that the new HAART regimen will be successful are increased since mutations conferring resistance to the spared class should not be present.

In the past few years, two types of resistance assays have been developed: the genotype analysis, which identifies specific mutations, and the phenotype analysis, which compares the drug sensitivity of the patient’s virus to wild-type virus. These assays are being studied to determine whether they can be helpful in guiding the choice of antivirals in patients who are failing HAART. Preliminary results from clinical trials show that the use of resistance assays can result in moderately lower viral loads in some situations.^10-12 Whether this added suppression will yield clinical benefit will only be determined with long-term follow up. In the community, these assays are often used, although they have not yet received FDA approval.

Metabolic Complications of HAART

Anti-retroviral agents have side effects and certain toxicities that usually manifest themselves early in the course of treatment. However, over the past few years, other complications have been described that develop much later. In some patients, changes in body habitus with fat accumulation in the trunk and/or fat wasting of the extremities, face, and buttocks have been described. This is termed "lipodystrophy." Since this manifestation was noted after the availability of protease inhibitors, they were initially considered the etiology of the disorder. However, recent investigations show that although lipodystrophy is seen more commonly in patients on protease inhibitors, it can also be seen in patients on non-nucleoside reverse transcriptase inhibitors and occasionally in patients on no therapy.¹³

The mechanism of the disorder is not known. Observational studies have shown that the disorder may be a consequence of successful therapy, since patients with lipodystrophy are more likely to have been on long-term HAART and have viral load suppression.¹⁴ Studies where patients who were on protease inhibitors were switched to another drug class have not shown resolution of the lipodystrophy.^15,16

Other metabolic abnormalities that have been associated with protease inhibitors (and perhaps HAART in general) are insulin resistance and lipid abnormalities (increases in cholesterol and triglyceride levels). Mitochondrial toxicity is being theorized as the mechanism by which nucleoside analogues may give rise to certain side effects (pancreatitis, peripheral neuropathy, myopathy, hepatic steatosis and lactic acidosis).

Only when the mechanisms of these metabolic abnormalities are understood will it be possible to conclusively determine their cause. At this time, the benefit of HAART outweighs the risk of lipodystrophy, which primarily remains a cosmetic handicap. However, if pancreatitis, lactic acidosis, or hepatic steatosis occurs, therapy should be discontinued and a different regimen considered after resolution.

Use of HAART in Pregnancy

Pregnant women who are infected with HIV have a 25 percent to 30 percent risk of transmitting HIV to their baby. Transmission usually occurs at the time of delivery, but may occur earlier. The higher the mother’s viral load, the higher the risk of transmission. It has been demonstrated that treatment of the mother can decrease the risk of transmission to the baby. In 1994, the ACTG 076 study showed that AZT reduced HIV transmission by 67 percent.¹⁷

Since the publication of the ACTG 076 trial, the U.S. Public Health Service has recommended that all pregnant women be counseled regarding HIV. California has enacted a law that requires such counseling and the offering of an HIV test.¹⁸ The California Legislature is considering enabling routine HIV testing of pregnant women.

The trials from the mid 1990s studied AZT monotherapy, however this is now considered to be suboptimal therapy. Combination therapy has become the standard of care for nonpregnant patients infected with HIV. There has been some hesitance to use combination antivirals in pregnancy due to the unknown risks of these drugs to the fetus. Recent reports from academic centers using combination therapy in pregnancy report perinatal transmission rates of less than 2 percent. No increased fetal abnormalities have been reported, however long-term follow up is not available. Therefore, it is now recommended that a pregnant woman with HIV receive HAART therapy. This should improve the health of the mother and decrease transmission to the baby. The CDC has issued guidelines on the use of anti-retrovirals during pregnancy that are regularly updated as new information becomes available.¹⁹

Opportunistic Infections

Opportunistic infections occur when there is profound immune suppression. Since the widespread use of HAART, the incidence of AIDS and AIDS-related opportunistic infections has decreased. When patients with early HIV infection are put on HAART, the immune deterioration associated with HIV is delayed, so the incidence of opportunistic infections in this population has decreased. When patients with advanced disease are put on HAART, there is usually an increase in the CD4 lymphocyte count. This rise in CD4 cell count correlates with improved immune function (although it does not return to normal) and the risk for opportunistic infections declines. In patients who have low CD4 counts despite HAART, the incidence of opportunistic infections has declined because of adequate antibiotic prophylaxis.

Tuberculosis remains the most common HIV-associated infection worldwide. In the early 1990s, the incidence of TB dramatically increased in the United States. This was partially due to the increased prevalence of tuberculosis in HIV-infected patients. It is estimated that an HIV-infected individual with a positive skin test for TB is 100 times more likely to get an active TB infection compared to a person not infected with HIV. The risk of getting active TB is 7 percent to 10 percent per year whereas an HIV-negative person has a 5 percent to 10 percent risk in his or her lifetime.²⁰ Because of the large degree of overlap between these two epidemics, all patients with HIV need to be screened for TB. Conversely, any patient with active tuberculosis should be tested for HIV.^21,22

The incidence of sexually transmitted diseases declined significantly from the 1980s to the mid 1990s. This was especially marked in the risk category of men who have sex with men. The lower infection rates were thought to be a consequence of increased HIV awareness and intensive educational programs that were aimed at this group. Unfortunately, over the past few years, there has been a resurgence in STDs among men who have sex with men. Significant proportions of these patients are also infected with HIV. This higher STD rate correlates to an increase in high-risk unprotected sex. The laxity in safer sexual practices is attributed to a lower level of patient concern about contracting (and transmitting) HIV because of the availability of HAART.^23,24

Prevention

A vaccine to prevent HIV is still considered the best possible solution to curb this disease. Although much research is being done in this arena, no vaccine has yet been proven to be effective. Some of the obstacles in the way of the development of an effective vaccine include the large number of HIV strains, the ability of HIV to mutate and escape control, the difficulty of producing neutralizing antibodies, and the need for stimulation of cellular immunity.

Prevention of HIV will be the ultimate treatment of this disease. Education and behavior modification have been shown to reduce infection to an extent. Although antivirals have been a great boon; and many patients are alive because of these medications, the disease still has no cure. Patients in the Western world have been able to take advantage of HAART, but the majority of people with HIV live in poor areas of the world that have little or no access to these very expensive drugs. Worldwide, prevention rather than therapy remains the best strategy for dealing with the HIV pandemic.

Author

Geeta Gupta, MD, is an associate clinical professor of medicine in the Division of Infectious Diseases at the University of California at Irvine Medical Center.

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10. Baxter JD, Mayers DL, et al. A pilot study of the short-term effects of antiretroviral management based on plasma genotypic antiretroviral resistance testing (GART) in patients failing antiretroviral therapy. Sixth Conference on Retroviruses and Opportunistic Infections, Abs LB8, 1999.

11. Cohen C, Hunt S, et al, Phenotypic resistance testing significantly improves response to therapy: A randomized trial (VIRA3001). Seventh Conference on Retroviruses and Opportunistic Infections, Abs 237, 2000

12. Durant J, Clevenbergh P, et al, Drug-resistance genotyping in HIV-1 therapy: The VIRADAPT randomised controlled trial. Lancet 353(9171):2195-9, 1999.

13. Miller JE, Emery S, et al. The Australian prevalence survey of lipodystrophy syndrome. Seventh Conference on Retroviruses and Opportunistic Infections, Abs 201, 2000.

14. Clinical factors related to the severity of fat redistribution in the HIV Outpatient Study. Seventh Conference on Retroviruses and Opportunistic Infections, Abs 23, 2000.

15. Ruiz L, Negredo E, et al, Clinical, virological, and immunological benefit of switching the protease inhibitor by nevirapine in HAART-experienced patients suffering lipodystrophy: 36-week follow-up. Seventh Conference on Retroviruses and Opportunistic Infections, Abs 206, 2000.

16. Carr A, Cooper DA, Randomized, multicenter study of protease inhibitor substitution in aviremic patients with antiretroviral lipodystrophy syndrome. Seventh Conference on Retroviruses and Opportunistic Infections, Abs 205, 2000.

17. Connor IM, Sperling RS, et al, Reduction of maternal-infant transmission of HIV type 1 with zidovudine treatment. N Engl J Med 331:1173-80, 1994.

18. California State Law; Chapter 873, Statutes of 1995; SB 889. 1995.

19. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. http://www.hivatis.org, Feb 25, 2000.

20. Selwyn PA, Hartel D, et al, A prospective study of the risk of tuberculosis among intravenous drug users with HIV infection. N Engl J Med 320:545-50, 1989.

21. Gordin FM, Matts JP, et al. A controlled trial of Isoniazid in persons with anergy and HIV infection who are at high risk for tuberculosis. N Engl J Med 337:315-20, 1997.

22. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: Principles of therapy and revised recommendations. MMWR 47(RR-20):1-58, 1998.

23.Resurgent bacterial sexually transmitted disease among men who have sex with men -- King County, Washington, 1997-1999. MMWR 48, No 5:773-7, 1999.

24. Increases in unsafe sex and rectal gonorrhea among men who have sex with men --San Francisco, California, 1994-1997. MMWR 48(3):45-8, 1999.

To request a printed copy of this article, please contact/Geeta Gupta, MD, UC Irvine, Department of Medicine, Irvine, CA 92697-4081.

Figure 1.

Figure 2.

Table 1. Antiretroviral Drugs

*FDA approval was expected in late 2000.

** Significant drug interactions occur with protease inhibitors