Strategies In Antiretroviral Therapy

Gerald Horton, M.D.
Gerald Horton, M.D. is a Family Practitioner and a Senior Physician with the
Duval County Health Department. He is a consultant and/or serves on the
speakers bureau for Glaxo-Wellcome, Merck, and Roxone Laboratories.

Introduction

The Human Immunodeficiency Virus is the causative agent of HIV/AIDS. In the United States most cases of HIV/AIDS are attributable to HIV-1. In Africa HIV-2, a related virus with a similar mode of transmission, is an important cause of HIV/AIDS. Specific antibodies to each are recognizable and can be used to document the presence of infection. HIV specific antibodies are demonstrated using two testing modalities. A screening test, the HIV Elisa, is a sensitive screening tool; however, the false-positive rate is sufficiently high enough to require a less sensitive but more specific test such as the Western Blot or IFA (immuno-flourescent assay) to confirm the diagnosis of HIV infection. During the first few weeks after infection these HIV specific antibodies may not be present creating a window in which serologic evidence of HIV infection can not be found. In some patients viral proteins such as p24 can be detected within days of infection though these levels fall to undetectable levels as the immune system responds to HIV infection. HIV RNA can also be detected in patients before the development of HIV specific antibodies; current standards require the Elisa and Western blot test to provide unequivocal proof of HIV infection. Newer assays such as nuclear antigen testing are under investigation to improve the ability to diagnose HIV infection in its earliest stages.

Primary HIV Infection

As many as 50-90% of persons exposed to HIV will be symptomatic as viral infection disseminates. A constellation of symptoms referred to as the Acute Retroviral Syndrome is often described as a "flu-like" illness with fever, generalized lymphadenopathy, pharyngitis, myalgias, retrorbital cephalgia, nausea, vomiting and diarrhea. There is variable expression of these symptoms among patients. A maculopapular rash is noted in more than 70% of individuals. Oral and genital ulcerations are present in 10-20% and 5-15% of patients respectively. These symptoms and physical examination findings coupled with a high index of suspicion in at risk populations allow the opportunity to diagnosis the primary HIV infection.

HIV is a neurotrophic virus and may cause severe neurologic manifestation in primary HIV infection such as aseptic meningitis, encephalitis, Guillan-Barre syndrome, and cranial or peripheral neuritis/neuropathy. In a limited number of patients opportunistic infections such as esophageal candidiasis, cerebral toxoplasmosis, and Pneumocystis carinii pneumonitis are seen in primary HIV infection.

Laboratory abnormalities of lymphopenia, thrombocytopenia and elevated hepatic enzymes are often present in primary HIV infection. Rhabdomyolysis and elevated creatinine phosphokinase have also been described.

HIV Quantification And The Immune System

HIV preferentially binds to CD4 receptors of a variety of cells. HIV can only replicate in limited cell types. Infection and resultant cell death of CD4 bearing T lymphocytes leads to progressive immune dysfunction. This effect may be quantified by measuring the CD4 T cell count. Normal CD4 T cell counts in the non-HIV infected patient range from 800 to 1200 cells/mm3. Primary HIV infection yields an initial fall in CD4 T cell counts as low as 200 cells/mm3 but usually recovery occurs and CD4 T cell counts rebound to within 200 of pre-infection levels. There are other mechanisms of CD4 T cell loss involving autoimmune phenomena, cytokine mediated pathways and apoptosis.

HIV itself may be quantified with the use of two different tests. Plasma viral loads of HIV can be measured with either the PCR (polymerase chain reaction) or bDNA (branched DNA) assays. These assays can also be applied to other specimens such as lymph node extracts, cerebrospinal fluid and genital secretions. Since their initial introduction into clinical practice these tests have been improved both in reproducibility as well as sensitivity. Both assays now have lower limits of detection (PCR <13-25 copies and bDNA <50 copies) than earlier versions. Plasma viral loads are best measured serially with one of the two assays. PCR derived viral loads are approximately 1.8 fold higher than bDNA derived viral loads.

There are three patterns of disease progression that can be distinguished on the basis of serial CD4 T cell counts and plasma viral loads as well as clinical symptoms. The most common pattern seen in the majority of patients is one of gradual decline in CD4 T cell counts approximately 40-80 cells per year in untreated individuals. In this pattern patients have 8-10 years where they appear to be minimally symptomatic or asymptomatic. In a small subgroup of patients (rapid progressors) CD4 cell counts fall precipitously and opportunistic infections or malignancies ensue leading to death. Conversely, some patients have low or non-detectable plasma viral loads and preserved CD4 cell counts (long-term nonprogressors). Factors influencing progression of disease may encompass differences in viral strain pathogenicity, and host immune responses. Recently chemokine receptors (CKR5 and CXCR4) that act as coreceptors for HIV attachment to target cells have been discovered. Some individuals may be homozygous or heterozygous for the absence of CKR5 receptor and may be resistant to infection or have an altered disease course.

Initiation Of HIV Antiretroviral Therapy

Current guidelines from the Department of Health and Human Services and the International AIDS Society USA consider CD4 cell count, plasma viral loads, and clinical symptoms in the recommendations of when to initiate antiretroviral therapy. Prior to the availability of plasma viral load testing, the absolute CD4 cell count of 500 cells/mm3 was used by most clinicians for initiation of treatment. Now the plasma viral load test carries 60% of the weight and CD4 cell count 40% of the weight in the decision of when to initiate therapy. The range of 10,000-20,000 copies of virus/ml serves as a guide to recommend treatment and allows both PCR or bDNA measurements to be used in this decision process. Many variables need be considered before initiating therapy including risk of disease progression, ability to adhere to complex regimens, evolution of mutations, cost and toxicities of therapy.

Mechanisms Of Inhibition

Presently available antiretroviral drugs can be divided into protease inhibitors (Table 1) and reverse transcriptase inhibitors (Table 2) according to their site of action in HIV replication. Reverse transcriptase inhibitors (RTI's) can be further divided into three subsets: nucleoside analogues, nucleotide analogues, and non-nucleosides. HIV-1 as a retrovirus of the lentivirus subfamily encrypts it's genetic information in the form of RNA. HIV-1 Reverse transcriptase (RT) produces a complimentary DNA strand from the viral RNA, strips the RNA strand from the DNA strand and then matches a second complimentary strand of DNA to it. This proviral DNA is integrated into the host cell and serves a template for progeny virus production. Nucleoside and nucleotide reverse transcriptase inhibitors, after phosphorylation, compete with natural deoxynucleoside triphosphates for the active site of RT and then result in chain termination. Non-nucleosides are inhibitors of RT and bind to the active site in a non-competitive fashion.

Later in the viral life cycle, polyprotien precursors require cleavage to assemble virions. Near the cell wall protease is integral in the formation of mature virions. In the presence of a protease inhibitors, defective virions are formed which are unable to propagate HIV-1 infection. These two sites of inhibition of viral replication provide the initial rationale for highly aggressive anti-retroviral therapy, or HAART, by targeting both RT and protease. The dual target approach has allowed for critical potency responsible for the dramatic improvement in HIV morbidity and mortality seen since the introduction of protease inhibitors. However, the development of single-target regimens of sufficient potency might leave other salvage opportunities available in the event of initial regimen failure.

Initial Therapy Options

As currently defined, HAART requires combining two nucleoside reverse transcriptase inhibitors with one protease inhibitor. An acceptable option is to substitute a non-nucleoside for the protease in a triple drug regimen. The 1997 International AIDS USA guidelines cautioned that this option might not have the potency required to suppress viral replication in patients with high viral loads. Recent studies such as the Atlantic study and the Dupont 266-006 study do demonstrate the efficacy of these protease sparing regimens.

A third option for initial therapy has become available with the development of abacavir. This guanosine analogue has significantly more potency than the other members of its class and can be combined with 2 additional nucleoside analogues in what is referred to as a triple nucleoside regimen. This regimen focuses inhibition at a single target site. Data from M. Fischl et al in the CNA3003 study compared zidovudine/lamivudine to the triple combination of zidovudine/lamivudine/ abacavir. The triple nucleoside arm evidenced superior potency with a median 4.5 log drop in viral load. (This study started before the superiority of three drug regimens was universally accepted). There is still uncertainty of the potency of this triple nucleoside analogue regimen in patients with higher viral load i.e. >100,000 copies of RNA/ml as suggested by results of the CNA3003 study. In the CNA 3005 study however, patients were stratified into viral loads below 10,000, 10,000 to 100,00 and >100,000 and no significant differences were noted when a triple nucleoside regimen was compared with a protease/2 nucleoside based regimen.

The choice of initial regimen must take into consideration multiple factors. Different schools of thought exist with one favoring the most intensive regimen initially to prevent drug resistance from developing in patients who may not be completely suppressed by a less intensive regimen. Others advocate sequencing regimens based upon the combination of different drug classes in order to preserve future options as it is recognized that only 50-60 % of patients will be able to achieve long term control of viral replication with their initial regimen. In addition, long term metabolic consequences of HAART have been noted such as diabetes mellitus, dyslipidemias and a poorly understood fat redistribution syndrome (lipodystrophy). Switch studies in which patients are initially begun on protease inhibitor containing regimens then changed to protease-sparing regimens once viral suppression has been obtained are ongoing to understand these complications.

Intensification

The goal of therapy has been to drive the viral load as low as possible for as long as possible. Longitudinal studies disclose that the durability of a regimen correlates with suppression of viral load to below 25-50 copies of HIV RNA/ml. In patients who do not achieve complete viral suppression there are two opportunities in which to intensify regimens with additional agents: early (primary) and later (secondary). If the viral load fails to become undetectable within the 8-16 weeks after initiation, the addition of one of several agents may be able to drive viral loads down further. An additional reverse transcriptase inhibitor can place greater selective pressure on viral replication. This pressure may be seen in an additive fashion or by reversing resistance to one of the primary drugs, as seen when adefovir is used with zidovudine in the presence of the M184V mutation seen with lamivudine resistance. A second protease inhibitor in certain dual protease combinations can, via cytochrome P4503A4 inhibition, increase the serum concentration of the first protease inhibitor. This may overcome low level protease inhibitor resistance. Hydroxyurea is thought to potentiate the inhibition of RT by didanosine and possibly stavudine and abacavir. If viral suppression is attained initially and then lost, secondary intensification as depicted above may be successful in re-establishing undetectable viral loads. This is in contradistinction to adding one new drug to a failing regimen.

The definition of failure has evolved and one need delineate virilogic failure from immunologic failure. Previously, return of viral load to 50% of pre-treatment levels was termed virologic failure, but more recently viral rebound (documented on repeated testing) with as little as 2000-3000 copies of HIV RNA can be all that is needed before the re-thinking of the regimen is appropriate. Immunologic failure is measured by declining CD4 T cell counts or the development of opportunistic illnesses. Patients with low viral loads and stable CD4 T cell counts do derive continued immunologic benefit from their antiretroviral therapy. Occasionally discordant changes can be seen with stable or increasing CD4 cell counts in patient with high viral loads. This phenomena has yet to be explained.

Options For Salvage Therapy

The concept of salvage therapy was born from the failure of the classic 2 nucleosides and 1 protease inhibitor regimens. Old dogma suggested that after triple drug failure, one might switch the protease inhibitor and one or two of the nucleosides to regain control of viral replication; but information developed rapidly regarding cross resistance among drugs in their respective classes. This knowledge has led to the development of 4, 5, or more drug-containing salvage regimens. The first commonly accepted salvage regimens combined ritonavir and saquinavir with reverse transcriptase inhibitors. Herein lies another example of how cross-resistance between members of the same class affects clinical drug efficacy. Those regimens based on protease inhibitors with different resistance patterns from the salvage combination are more likely to be potent. The greatest success is seen when a salvage regimen contains an antiretroviral to which the patient's virus has not been exposed.

Mega HAART is the term used when patients are placed on as many drugs as they can tolerate. Though partial or full drug resistance may be suspected, it is hoped that some aggregate benefit may be obtained either by lowering the viral load to an acceptable level where immunological deterioration is not as severe, and/or by the selection of mutant forms which may not be as pathogenic as wild-type virus. This approach is usually limited by toxicity, but may be the only option for some patients.

Summary

Although our understanding of HIV viral dynamics has been improved, the management of antiretroviral therapy has increased in complexity. New agents are in development, such as additional protease and nucleoside analogues as well as non-nucleosides. Hopefully they will bring significant benefits in term of convenience and tolerability with different resistance patterns and target sites of action than the currently available agents. Injudicious choices of combinations can have drastic implications for future therapy option. Outcomes in terms of morbidity, mortality and quality of life can only be positively affected when a patient is managed in a thoughtful manner by physicians experienced in antiretroviral therapy.

References

Dolin R, Masur H, Saag M. AIDS Therapy. Churchill Livingstone, Philadelphia, PA. 1999.

Powderly W. Manual Of HIV Therapeutics. Lippencott Williams & Wilkins Publication. 1997.

Kuritzkes D. HIV Pathogenesis And Viral Markers, HIV Clinical Management Series. International AIDS Society. 1998.

Gallant J, Murphy R. Antiretroviral Therapy, HIV Clinical Management Series. International AIDS Society. 1998.

Coakley E, Inouye R, Hammer S. Update On Developments In Antiretroviral Therapy. International AIDS Society. 1998.

Jacksonville Medicine / August, 1999