Comparison of clinical and immulogical responses to Zidovudine (AZT) and Tenofovir (TDF) – containing ARV regimens in patients taking HAART at Roma health service area of Lesotho

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COMPARISON OF CLINICAL AND

IMMUNOLOGICAL RESPONSES TO

ZIDOVUDINE (AZT) AND TENOFOVIR (TDF) –

CONTAINING ARV REGIMENS IN PATIENTS

TAKING HAART AT ROMA HEALTH SERVICE

AREA OF LESOTHO.

BY

ADEBANJO ADEFOLARIN BABAFEMI

ADEBANJO ADEFOLARIN BABAFEMI

STUDENT NUMBER 15249484

Thesis submitted in partial fulfilment of the requirements

for the degree

M Med (Family Medicine)

At

Stellenbosch University

August 2010

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DECLARATION

I, Adefolarin Babafemi ADEBANJO, hereby declare that the work which I hereby submit as partial fulfilment for the degree MMed (Family

Medicine), on which this thesis is based, is original (except where

acknowledgements indicate otherwise) and that neither the whole work nor any part of it has been submitted, or is being submitted, for another degree at this or any other university.

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ABSTRACT

Objective: The objective of this retrospective cohort study is to assess

whether demographic and anthropometric parameters, laboratory tests, co-morbidity, co-infection, treatment regimen, IRIS and adherence to treatment predict the expected response to HAART and differences if any, in the pattern of response as measured by CD4 count, weight gain and haemoglobin levels in two cohorts of patients in Roma, The Kingdom of Lesotho.

Method: Data were collected randomly from a computerised database of the

Antiretroviral Centre of the hospital and two cohorts of 151 subjects in each of the two arms of the study were identified from hospital records from January 2008. Each of these subjects was followed up over a period of 12 months with data obtained for at least 2 visits within the 12 month span. Data were obtained at baseline, 3 months and also at 6 and 12 months marks. Data on characteristics were compared between the two arms. Variables that may be potential confounders were identified and univariate and multivariate logistic regression analyses were carried out to establish differences independent of confounding factors for the combined endpoints as well as for each endpoint separately.

Results: In all 302 patients had their records analysed and comparison of

clinical and immunological response patterns in patients taking AZT and TDF-containing ART regimens and the possible prediction of which the regimen would be better and within which population. Despite the perceived mismatch between two NRTIs it can be concluded from the results of this study that, overall, the inclusion of AZT in treatment regimen showed a modest protective effect over the TDF counterpart as measured by the endpoints of the discriminative powers of the Receiver Operating Curves of the explanatory variables being 66% 77% and 66% for CD4, Haemoglobin

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and Weight respectively, and 63% 70% and 65% for the same variables in the AZT and TDF arms of the study respectively.

Conclusion: In a population of HIV patients on treatment in resource-limited

settings AZT-containing regimens appear to show a slight improvement over the TDF-containing ones.

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List of tables

Table 3.1 Patient demographics for the AZT cohort at baseline.

Table 3.2 Patient demographics for the TDF cohort at baseline. Table 3.3 Other considerations on the AZT cohort.

Table 3.4 Other considerations on the TDF cohort.

Table 3.5 Univariate predictors of CD4 response at 12 months of therapy (AZT)

Table 3.6 Univariate predictors of weight response at 12 months of therapy (AZT)

Table 3.7 Univariate predictors of haemoglobin response at 12 months of therapy (AZT)

Table 3.8 Univariate predictors of CD4 response at 12 months of therapy (TDF)

Table 3.9 Univariate predictors of weight response at 12 months of therapy (TDF)

Table 3.10 Univariate predictors of haemoglobin response at 12 months of therapy (TDF)

Table 3.11 Adjusted Odds Ratios for retained variables for CD4 (AZT) Table 3.12 Adjusted Odds Ratios for retained variables for haemoglobin (AZT)

Table 3.13 Adjusted Odds Ratios for retained variables for weight (AZT) Table 3.14 Adjusted Odds Ratios for retained variables for CD4 (TDF) Table 3.15 Adjusted Odds Ratios for retained variables for weight (TDF) Table 3.16 Adjusted Odds Ratios for retained variables for haemoglobin (TDF)

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List of figures

Figure 3.1 ROC curve for AZT CD4 Figure 3.2 ROC for AZT haemoglobin Figure 3.3 ROC for AZT weight

Figure 3.4 ROC for TDF CD4 Figure 3.5 ROC for TDF weight

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Abbreviations

ACTG AIDS Clinical Trial Group

AIDS Acquired Immunodeficiency Syndrome

ANC Antenatal Care

ARV Antiretroviral

AZT Zidovudine

CEO Chief Executive Officer

ddC Zalcitabine

d4T Stavudine

DNA Deoxyribonucleic Acid

EDTA Ethylenediamine Tetraacetic Acid

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HAART Highly Active Antiretroviral Agents

HIV Human Immune Deficiency Virus

HLTV Human T-Lymphotrophic Virus

IRIS Immune Reconstitution Inflammatory Syndrome

LAV Lymphadenopathy-Associated Virus

MTCT Mother-To-Child Transmission

NGO Non-Governmental Organization

NNRTI Non-Nucleoside Reverse Transcriptase Inhibitor

NRTI Nucleoside Reverse Transcriptase Inhibitor

OIP Opportunistic Infection Prophylaxis

PCP Pneumocystis Pneumonia

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RNA Ribonucleic Acid

TDF Tenofovir

UNAIDS United Nations Programme on HIV/AIDS

VCT Voluntary Counselling and Testing

WHO World Health Organization

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Background

The burden that the HIV/AIDS pandemic has put on economies of countries particularly on the developing countries in sub-Saharan Africa as well as on infected and affected people necessitated the development of various interventions of which antiretroviral agents are principal. Worst hit countries of the world are still grappling with effective coverage of their various sub regions and have developed several programs to scale up the supply of antiretroviral agents, manage complications effectively and train various staff to perform these functions. However, it is not just enough to have indiscriminate roll-out of these agents to eligible individuals and have efforts made at ensuring proper adherence and adequate follow-up. Needless to say, similar efforts are needed to predict the possible outcomes of therapy prior to its commencement in eligible individuals, to determine the factors that drive response in some patients while similar responses are not seen in others. This will tend to improve overall outcome of patients placed on antiretroviral agents.

This study will look at an HIV cohort in a district hospital in Roma, a semi-urban region of Lesotho.

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retrovirusAIDShumans immune system virus[1,2]

blood semen vaginal fluid pre-ejaculate breast milk unprotected sexual intercourse birth developed world

pandemic As of January 2006 Joint United Nations Programme on

HIV/AIDS World Health Organization December

1

1981 pandemics[3]_Africa_economic

growth[4]_Africa_orphans[5]_{Antiretroviral}_mortality_morbidity[6]

human immune system helper T cells macrophages dendritic cells apoptosis CD8 cytotoxic lymphocytes cell-mediated immunity AIDS (Acquired Immunodeficiency Syndrome)[7]

June 5 1981 Centers for Disease Control and Prevention Pneumocystis pneumonia (PCP) Pneumocystis carinii Pneumocystis jiroveciiLos Angeles[8]_{Gay-Related Immune Deficiency}

Luc Montagnier Pasteur Institute France[9]_{Robert Gallo}_{United States}[10]_President

Mitterrand President Reagan[2]

Lentivirus[11]_Retroviridae[12][13]_RNA _viruses_genome_DNA_reverse

transcriptase integrase transcribed latent

Cameroon chimpanzees twentieth century[14][15]_{Sooty Mangabey}

Guinea-Bissau Gabon Cameroon[16]_{West Africa}[16]

 Democratic Republic of Congo[17]

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 [19]

[20]_{The Times}[21]

Tom CurtisRolling StoneOPV AIDS hypothesis Belgian Congo Hilary Koprowski polio vaccine[22]_libel_Edward _Hooper_The

Riverpolio vaccine chimpanzee simian immunodeficiency virus[23][24]

[3] [3]

Sub-Saharan Africa[3]_{South & South East Asia}_Asia[25]_{life expectancy}[26]

World Bank[27]

HAART[28]

vaccine post-exposure prophylaxis[29][30][31]_{anti-retroviral}_{nucleoside analogue}

reverse transcriptase inhibitors protease inhibitor non-nucleoside reverse transcriptase inhibitor[32]_{viral load}[33]

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[34,35][36]_morbidity[31,37,38][39]_median[40][41][42,43,44]_{lipodystrophy}_{dyslipidaemia}_insulin

resistance cardiovascular birth defects[45,46]

[47,37][48][49]

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it is the thinking of most lay people and

especially HIV-infected persons that once

antiretroviral agents have been commenced

then a patient is on his way to full recovery.

Unfortunately, health workers in the field of

HIV/AIDS who sometimes inappropriately

initiate patients on treatment sometimes

echo this sentiment. Despite good measures

of community based motivation and

extensive education on the concept of

antiretroviral agents, there still remains that

erroneous impression that whatever time a

patient is started on therapy and regardless

of duration or extent of illness, the patient

was bound to recover fully. We want to know

who will respond and who wouldn't. In

addition this type of study has never been

done in this part of the country. Aim: To

study the response pattern and the

differences in response to antiretrovirals in

the 2 cohorts over a 12 month period.

Objectives: To assess whether

anthropometric parameters, laboratory tests,

co-morbidity or co-infection with

opportunistic agents, treatment regimen,

IRIS and adherence predict response to

HAART as measured by CD4 count, weight

gain and functional status over a time period

of one year.

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semi-urban region of The Kingdom of Lesotho

Retrospective Cohort Study Design.

      

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Patients with CD 4 count of > 200 cellsPatients not initiated on treatment within the study periodDefaulters of treatment (did not participate in treatment for at least 6 months).Patient selection and sampling frameSample of patients consists of a cohort of 302 adult subjects initiated on antiretroviral therapy from January 2008. Subjects in this study are essentially cases detected in the out-patient department, those detected on in-out-patient basis and those identified during routine community-based screening exercises. The subjects selected for the study were divided into two arms each representing a separate group of the study based on the HAART regimen they were placed.Identification of casesSubjects in the cohorts qualified as cases if they were eligible and already started on HAART as at the time the study began and continued on treatment regardless of hospital admission or therapy for co-morbidities during the period from January 2008 to January 2009 as confirmed by hospital (PHC)claims data. Patients were identified as defaulters of treatment if they did not have at least two follow up visits during the course of this study and were not eligible to become cases. Also excluded from the study were patients who were lost to follow up. The ART center database was used to identify patients who died or defaulted during this period.Measurement of covariatesThe following data was retrieved from the membership, authorisation for medicine and hospitalisation claims databases for each of the cases:Demographic covariatesAge (measured on the 1st of January 2008 in years)Gender (male or female) Covariates indicating opportunistic infections conditionsThese covariate data regarded as input variables for the purposes of this study were determined from chronic medication authorisations and database and are non-mutually exclusive (0 = condition not registered; 1 =

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0. 00 0. 25 0. 50 0. 75 1. 00 S en si tiv ity 0.00 0.25 0.50 0.75 1.00 1 - Specificity

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Human immunodeficiency virus (HIV) is a

that causes acquired immunodeficiency

syndrome (), a condition in in which the

begins to fail, leading to life-threatening

opportunistic infections. Previous names for

the include human T-lymphotropic virus-III

(HTLV-III), lymphadenopathy-associated virus

(LAV), or AIDS-associated retrovirus (ARV).

Infection with HIV occurs by the transfer

of , , , , or . Within these bodily fluids, HIV is

present as both free virus particles and virus

within infected immune cells. The three

major routes of transmission are ,

contaminated needles, and transmission

from an infected mother to her baby during

pregnancy or at , or through breast milk.

Screening of blood products for HIV in the

has largely eliminated transmission through

blood transfusions or infected blood products

in these countries.HIV infection in humans is

now in certain geographic areas . , the

(UNAIDS) and the (WHO) estimate that AIDS

has killed more than 25 million people since

it was first recognized on , , making it one of

the most destructive in recorded history. In

2005 alone, AIDS claimed an estimated 2.4–

3.3 million lives, of which more than 570,000

were children. It is estimated that about

0.6% of the world's living population is

infected with HIV. A third of these deaths are

occurring in sub-Saharan, retarding and

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Comparison of clinical and immulogical responses to Zidovudine (AZT) and Tenofovir (TDF) – containing ARV regimens in patients taking HAART at Roma health service area of Lesotho