The role of CD4 count and viral load tests in monitoring HIV positive Patients

Abstract

Viral load Measurement is the mainstay to indentify viral replication. Estimating viral load is the best in discriminating between treatment failure, non-adherence, and can serve as a proxy for the risk of transmission of the HIV virus at the population level. In the absence of viral load testing, immunological monitoring is considered to indicate treatment failure, although falls in CD4 count correlate poorly with virological failure. However, in the absence of viral load and CD4 tests, syndromic management of human immunodeficiency virus could be used to indicate the need for treatment switching. Medical doctors are advised to desist in applying syndromic management of HIV where, CD4 count is possible, laboratory values of CD4 count must be obtained before certain treatment option is indicated. The HIV resistance testing is not always practicable in developing countries due to lack of second or third choice therapy and due to economic reasons.

Keywords: HIV, CD4 count, Viral load.

Introduction

The Virus causing AIDS was first isolated in 1983 by Dr. Montagnier of France, and, later, in 1984 by Gallo and Levy of the United States of America. However, the name of the virus (Human Immunodeficiency Virus) was given at the international conference in 1986. The virus isolated in West Africa was termed HIV-2, and HIV- 1 was given to the former. HIV is categorized to the rentivirus, subfamily of the retrovirus, and a mature virus has a D- type particle with a diameter of 110nm. It is an RNA virus, has capsid around the core and an envelope outside the capsid. HIV penetrates into cells by binding of the envelope"s gp120 with CD4 antigen on the surface of the helper T- lymphocytes. The viral RNA is transformed to DNA by reverse transcription, done by enzymatic reactions and integrated to chromosomal DNA of helper T lymphocytes. Genomic DNA of HIV contains nine genes mostly gag, pol, env, tat, rev, nef, vif vpu and vpr between both ends. HIV attacks CD4 helper cells as a target and destroys it.

HIV remains one of the leading causes of infectious disease worldwide. It is devastating in terms of costs, death, human suffering, lowering of life expectancy by decades, children orphan and loss of income. The World Health Organization data (2013), showed that 35 million people are currently living with HIV. The number of people newly infected with HIV in 2013 was a total of 2.1 million people, out of these, adults was 1.9 million, while children was 240,000. The death burden of AIDS in 2013 was 1.5 million, and adults was 1.3 million, while 190,000 were children ages about 15 years on average. The HIV/AIDS pandemic crisis is far from over and policy makers and various governmental agencies should make policies on strategic means for more funding, preventive measures, Laboratory testing, and treatment program. In 2013, about 2 million people newly enrolled for antiretroviral treatment, this is the largest ever annual increase. The percentage of children in need of treatment in 2013 was 23 % compared to adults of about 37%. However, 67% of pregnant women living with HIV received treatment in 2013 to prevent vertical transmission. Dr. Richard Feachem on Rice University speech in 2003 said, "Most of what we once thought we knew about global health, has been proved wrong by the relentless advances of HIV/AIDS, tuberculosis, and Malaria…….there can be no more urgent cause facing us today. In Africa, the enemy is already among us, In Asia; the enemy is at the gates. “

Role of CD4 count and Viral load in monitoring HIV pandemic

Proper laboratory based diagnostics for screening, diagnosis, treatment initiation, and the monitoring of treatment efficacy are critical in managing the disease and reducing the number of new infections each year. The goal of providing Antiretroviral therapy (ART) is to suppress HIV to undetectable levels for life. Viral suppression therefore, reduces illness, death, the development of drug resistance, and the spread of new infections. When HIV is undetectable, it means that the virus is not replicating, and people can live healthy and productive life.

However, to determine when treatment should be started and whether treatment is working, two most important diagnostic tests are CD4 count (absolute and percentage), which measures the strength of the body´s immunological response, and HIV viral load test, which measures the amount of viral replication in the blood. These tests must be carried out by qualified Medical laboratory scientist, and effective treatment procedure results in a very low (undetectable) viral load and CD4 count within the normal range.

CD4 testing is a form of immunological monitoring and is mostly effectively used in deciding whether and when to start HIV treatment. CD4 count in developing countries today is mainly laboratory based and due to shortage of qualified medical laboratory scientists, results are delayed due to excessive work load, and this leads to delay in making appropriate treatment decisions by the Physician. The adoption of Point- of – care (POC) CD4 testing has accelerated treatment initiation and reduces the number of patients lost to follow up while test results are awaited.

Viral load monitoring is the optimal tool to determine if treatment is working and has long been the standard of care for treatment monitoring in developed countries. HIV treatment once started, must be taken for the rest of life, and routine treatment monitoring is necessary to ensure that a person`s ART regime continues to be effective. If the treatment stops working, the patient becomes sick and the risk of drug resistance and transmission is increased. The first indicator that a patient is no longer under optimal care is a detectable viral load – thus, the best and earliest indicator that a clinical intervention is needed is the viral load measurement.

Point – of – care (POC) testing apparatus refers to medical testing at or near the point of care, conducted within a very short time, for example, 10 to 30 minutes of sample collection, and followed by an immediate medical decision based on the results. POC testing eliminates delay associated with waiting for the laboratory based test results. POC diagnostics support early treatment and rapid initiation. However, depending on the context and the number of patients, POC may not be appropriate for every setting. Furthermore, POC testing must be monitored by the medical Laboratory scientist and must obey testing site neutrality. What then, is this testing site neutrality? This means that, it does not matter where the diagnostic test is performed or who performs the test, whether medically trained or not: all testing sites must follow the same regulatory requirements based on the complexity of the test. The complexity of implementing viral load technology in developing countries as well as higher upfront costs compared to other diagnostic technologies, has so far hindered adoption in developing countries and high HIV prevalence settings, where access to optimal treatment monitoring remains dismally low.

CD4 testing is recommended to measure immunological function after initiating ART, to confirm that CD4 cells have reconstituted and remain in an acceptable range (always above 500 cells/&µl, but definitely above 200 cells/&µl), a normal CD4 count ranges from 500 to 1000 cells/mm3. A CD4 count fewer than 200 cells/mm3 is one of the qualifications for AIDS diagnosis. CD4 cell count is not particularly effective for long time treatment monitoring. CD4 count cannot detect early signs of adherence problem or treatment failure because CD4 count naturally fluctuates a great deal and measuring CD4 count cannot detect the source of the problem – increasing viraemia. The absolute CD4 count is a calculated value based on the total of white blood cell count and the percentages of total and CD4+ T- lymphocytes. Thus absolute number may fluctuate in individuals or may be influenced by factors that may affect the total WBC and lymphocyte percentages, such as use of bone marrow suppressive medications or presence of acute infections. Splenectomy or co-infection with human T lymphocyte virus type1 may cause misleading elevated CD4 counts. Alpha-interferon also may reduce the absolute CD4 count without changing the CD4 percentage. In all these cases, CD4 percentages remain stable and may be a more appropriate parameter to assess a patient"s immune function. Treatment efficacy should result in an undetectable viral load within six to twelve months after ART treatment initiation; a detectable viral load after this period shows that treatment is not effective and could be falling. CD4 testing do not offer timely enough information to initiate an optimized treatment response, therefore, the eleven country MONET clinical trials on treatment simplification reported that if treatment was effective and viral load was suppressed, CD4 monitoring offered no added value. The recent research work of Gale et al 2013 reported that patients with CD4 count = 300 cells/&µl had almost 97% probability of retaining durable CD4 count =200 cells/&µl for four years, if their viral load stayed below 200 copies/ml, and this was increased to 99% if non- HIV causes of CD4 cell drop was excluded.

Viral load monitoring coupled with enhanced adherence support, helps deliver improved health outcomes both for the individual patients by reducing morbidity and mortality, and for the particular communities by reducing transmission of the HIV virus from one person to another. Viral load is fundamental for treatment initiation with patients initiating treatment at very high viral loads (=100,000 copies/ml) despite having high CD4 counts. Why? This is because ongoing HIV replication is very harmful. However, viral load testing is the standard of care in wealthy nations, routing virological monitoring is a mirage or sparsely available in poorly depressed economic nations, owing to costs, complexity, and scarcity of trained medical laboratory scientists. The highest measure of viral load can be over 500,000 copies/ml while the lowest levels of detectable viral load can be 40 to 75 copies/ml. Low viral load means lower amount of HIV activity. The primary goal of ART is to lower the viral load to levels below 40 to 75 copies/ml. It is pertinent to note that just because viral load may fall below these levels, does not represent that HIV is gone from the body.

Viral load testing remains undisputedly a gold standard for treatment monitoring in various ways:

• Ensures treatment efficacy: It detects adherence problems early, often before drug resistance develops. It prolongs the use of more affordable, well tolerated one – pill – a – day first line drug.

• Supports treatment adherence: Viral load triggers need for intensive adherence counseling that can result in viral re-suppression and contributes to treatment literacy and motivation to reach and maintain an undetectable viral load. Once non adherence has been addressed, enables early and specific confirmation of treatment failure due to drug resistance mutations. Virological testing enables time switching to a more effective drug regime, before drug resistance mutations accumulate and reduce the efficacy of second and third line regimes. It identifies risks of vertical transmission during pregnancy, breast feeding and between sexual partners.

• Identifies early risk of treatment failure: Viral load testing prevents unnecessary switches, based on non-specific immunological monitoring, to more expensive second line drugs.

The world Health Organization in 2013 recommended that antiretroviral therapy be started at once, regardless of CD4 count for seropositive patients that are pregnant, breast feeding, active tuberculosis, and severe hepatitis B virus, HIV positive in a serodiscordant relationship and in children under 5 years of age. In adults and adolescents, however, a CD4 count of 350 cells/mm3 was an indicator for urgent treatment in 2010, but, in 2013, this was extended to include patients with CD4 count of 500 Cells/mm3.There are a number of factors to consider when taken decisions on what antiretroviral combination to give to patients. The first combination of drugs that a patient takes is called first line therapy. Furthermore, an effective HIV therapy for seropositive patients should have a combination of three drugs, which are divided into five different classes. The World Health Organization advised in 2013, that an antiretroviral combination that consists of two drugs from Nucleoside/Nucleotide Reverse Transcriptase inhibitor class and another drug from the Non-Nucleoside Reverse Transcriptase inhibitor class be taken.

In developing nations, facilities to measure viral load and CD4 count are mainly unavailable, in this case; therefore, medical officers will depend on World Health Organization clinical staging of HIV disease. These clinical staging are divided into four stages. HIV diseases based on clinical symptoms are never accurate, grossly unreliable, and present errors associated with mis-diagnosis. They are mainly applicable to adults and adolescents, and are stated as:

Clinical Stage 1: It consists of asymptomatic, Persistent generalized lymphadenopathy etc.

Clinical Stage 2: Here, we have unexplained weight loss, recurrent respiratory tract infections, Herpes zoster, Angular chelitis, recurrent oral ulceration, popular pruritic eruptions, dermatitis, fungal nail infections, etc.

Clinical Stage 3: In this stage, there are; severe bacterial infections, pulmonary tuberculosis, Oral hairy leukoplasia, Persistent oral candidiasis, unexplained anemia, neutropenia, and or thrombocytopenia, Persistent fever more than a month, chronic diarrhea more than a month and unexplained severe weight loss, etc.

Clinical Stage 4: HIV wasting syndrome, Pneumocytis pneumonia, extra- pulmonary tuberculosis, Kaposi sarcoma and HIV encephalopathy etc.

Treatment should start as soon as the HIV positive patient is showing clinical syndromes of stage 3 or stage 4. These clinical stages are identified typically by the emergence of opportunistic infections and certain cancers, which a healthy immune body would normally fight off.

Conclusion

The introduction of efficient diagnostic equipment for screening and monitoring of HIV positive patients have revolutionized the HIV pandemic infection. The introduction of CD4 count, and viral load scientific tests, have reduced medical errors associated by the use of clinical staging treatment method, while, antiretroviral therapy has brought tremendous and sporadic changes in ensuring that HIV positive patients could live a normal life style. The point- of- care CD4 initiative have made a paradigm shift in improved retention to care and reduced workload in traditional laboratories and loss to follow up of these patients. Once again, medical doctors are advised not to depend on trial and error method of clinical staging, but, instead, seek laboratory oriented values of viral load and CD4 count as soon as possible before initiating ART to all seropositive patients. If viral load testing is provided by all developing nations, the seropositive patients globally will enjoy healthy prolonged lives, and the HIV conflict will be reduced. The better and effective utilization of global fund for HIV program by various governmental agencies of developing countries, and adequate pricing of laboratory reagents, equipment, and re-training of qualified medical laboratory scientists, there could be a cost effective solution to the general burden of HIV financial crisis.

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Autor:

Dr. Peter Ubah Okeke,

Ph.D, AMLSCN

Ministry of Health, Cape Verde