Challenges facing HIV treatment in Guinea-Bissau: the benefits of international research collaborations.

PROBLEM: The introduction of antiretroviral therapy (ART) for HIV infection in sub-Saharan Africa has improved the quality of life of millions of people and reduced mortality. However, substantial problems with the infrastructure for ART delivery remain. APPROACH: Clinicians and researchers at an HIV clinic in Guinea-Bissau identified problems with the delivery of ART by establishing a clinical database and by collaborating with international researchers. LOCAL
SETTING: The Bissau HIV cohort study group was established in 2007 as a collaboration between local HIV physicians and international HIV researchers. Patients were recruited from the HIV clinic at the country's main hospital in the capital Bissau. RELEVANT CHANGES: Between 2005 and 2013, 5514 HIV-positive patients were treated at the clinic. Working together, local health-care workers and international researchers identified the main problems affecting ART delivery: inadequate drug supply; loss of patients to follow-up; and inadequate laboratory services. Solutions to these problems were devised. The collaborations encouraged local physicians to start their own research projects to find possible solutions to problems at the clinic. LESSONS LEARNT: The HIV clinic in Bissau faced numerous obstacles in delivering ART at a sufficiently high quality and patients' lives were put in jeopardy. The effectiveness of ART could be enhanced by delivering it as part of an international research collaboration since such collaborations can help identify problems, find solutions and increase the capacity of the health-care system.

Introduction

In sub-Saharan Africa, the introduction of antiretroviral therapy (ART) for patients with human immunodeficiency virus (HIV) infections has improved the lives of millions of people and decreased mortality. However, despite support from the Global Fund to Fight AIDS, Tuberculosis and Malaria and other donor organizations, the infrastructure for delivering ART in low-resource settings is still affected by substantial problems. Earlier diagnosis and more aggressive treatment of opportunistic disease could decrease mortality beyond that achieved by ART alone. Moreover, as the use of ART has increased, there have been reports of drug stocks running out because of insufficient human resources or poor infrastructure. In addition, frequently the means of monitoring the effects and side-effects of ART are not available.

The aim of this article was to reflect on the challenges faced in the field at an HIV clinic in Guinea-Bissau. Principally, we wanted to describe how an international research partnership helped identify clinical problems and find solutions while, at the same time, building the capacity of the health-care system to deal with an HIV epidemic in a vulnerable country.

Local setting

Guinea-Bissau is located in western Africa and is one of the poorest countries on the continent. It gained independence from Portugal in 1974 after a war of liberation that caused tremendous damage to the country’s economic infrastructure. Since then, it has experienced considerable political and military upheaval. Unlike most countries in the subregion, Guinea-Bissau has experienced an increase in the spread of HIV-1 infection in recent years. In 1989, the country had the highest prevalence of HIV-2 infection ever reported whereas HIV-1 infection was nonexistent. However, the prevalence of HIV-2 infection is now decreasing, while that of HIV-1 infection is on the rise.,

In 2005, a national HIV programme was implemented in Guinea-Bissau by the Ministry of Health. However, it was only during 2007 that the programme led to an increase in the number of patients being treated. The Bissau HIV cohort study group was established in 2007 by the Bandim Health Project in Guinea-Bissau and Aarhus University Hospital in Denmark in collaboration with nurses and physicians from the Hospital Nacional Simão Mendes, which is Guinea-Bissau’s main hospital and is located in the capital Bissau. The Bandim Health Project is a member of INDEPTH, which is a network of 42 demographic surveillance system field sites in 20 countries in Africa and Asia. Since 1978, a demographic surveillance system established in Bissau by the Bandim Health Project has generated population and health data at the household level as part of a collaboration between the Ministry of Health in Guinea-Bissau and the Statens Serum Institut in Denmark. All patients with HIV infections who attended the HIV clinic at Hospital Nacional Simão Mendes were eligible for inclusion in the Bissau HIV cohort. The cohort study group created a database for all patients in the cohort and set up a biobank where blood samples from these patients were stored for use in research. The purpose of the database and the biobank was to help study how clinical, virological and immunological parameters influence the effectiveness of therapy.

Following the establishment of the Bissau HIV cohort study group, two doctoral students and 10 master’s students from Denmark, Iceland and Spain have worked at the HIV clinic for one to two years each and senior Danish researchers have visited on a regular basis. The close collaboration at the clinic between local HIV physicians and international HIV researchers provided a unique opportunity for sharing experience. The study group is supported financially and scientifically by the International Epidemiologic Databases to Evaluate AIDS network and the West African Platform for HIV Intervention Research. In addition, Danish universities and several Danish funding organizations have also provided financial support for research activities, including salaries for local staff and international researchers. Consequently, the study group is involved in collaborations both between developed and developing countries and between developing countries in Africa.

Relevant changes

Between June 2005 and June 2013, 5514 patients older than 15 years were diagnosed with HIV infections and were offered care at the HIV clinic at the Hospital Nacional Simão Mendes (Table 1). All medical consultations, laboratory investigations and treatment were free of charge. Information on these patients was stored in the clinical database created by the Bissau HIV cohort study group and blood samples were stored in the associated biobank.

Table 1

Patients attending an HIV clinic, Guinea-Bissau, 2005–2013

Characteristic	No. (%)a of patients (n = 5514)
Sex
Female	3590 (65)
Male	1922 (35)
Missing data	2 (0.04)
Age at first visit in years, median (IQR)	36 (29–45)
Type of HIV infection
HIV-1	3697 (67)
HIV-2	954 (17)
HIV-1 and HIV-2	598 (11)
Missing data	265 (5)
Included in the Bissau HIV study cohort
Yes	3699 (67)
No	1815 (33)
Baseline CD4+ T-lymphocyte count in cells/μL, median (IQR)	197 (79–375)
Started on ART
Yes	3170 (57)
No	2344 (43)

ART: antiretroviral therapy; CD4: cluster of differentiation 4; HIV: human immunodeficiency virus; IQR: interquartile range.

a All values represent absolute numbers and percentages unless otherwise stated.

The delivery of ART involved a multitude of challenges at the clinic; these were identified during daily clinical work and routine data entry into the database as well as during ongoing research projects. These problems, their effects and proposed solutions are presented in Table 2. Local staff had heavy workloads and many of these problems would not have been identified in the absence of collaborative research with organizations in other countries.

Table 2

Problems with ART delivery at an HIV clinic, Guinea-Bissau, 2005–2013

Problem	Effect	Solution
Inadequate drug supply	Patients with a high CD4+ T-lymphocyte count experienced Stevens–Johnson syndrome on switching from efavirenz to nevirapine after stocks of efavirenz ran out;8 development of drug resistance due to treatment interruptions	Improve stock management, increase investment in health-care infrastructure and capacity
Clinic relocation	Patients lost to follow-up	Increase the focus on HIV infection at the hospital to give the disease a higher priority among policy-makers
Widespread loss to follow-up	Patients not adequately treated	Identify risk factors for patients being lost to follow-up so that effort can be focused on the most vulnerable;9 introduce educational activities for patients to improve health literacy; telephone patients who are late for appointments; visit patients lost to follow-up at home
Poor treatment adherence	Treatment failure and drug resistance	Identify risk factors for poor adherence;10 improve health literacy
Laboratory inadequacies
Inadequate validation of HIV rapid tests	Errors in discriminating between infection with HIV-1, HIV-2 and both HIV-1 and HIV-2 occurred with the SD Bioline HIV 1/2 3.0 rapid test (Standard Diagnostics Inc., Yongin, Republic of Korea);11 ineffective treatment for HIV-2 infection using non-nucleotide reverse transcriptase inhibitors; expensive treatment for HIV-1 infection using protease inhibitors	Use other rapid HIV diagnostic tests
Temporary unavailability of biochemical tests and CD4+ T-cell count measurements	Delayed initiation of ART; late diagnosis of treatment failure; adverse events not diagnosed	Increase awareness of possible treatment failure
No HIV-RNA monitoring	Late diagnosis of treatment failure; development of drug resistance	Increase the ability of the laboratory to perform HIV-RNA measurements
Insufficient tuberculosis screening	Tuberculosis not diagnosed, leading to no tuberculosis treatment and increased mortality; no detection of drug-resistant tuberculosis	Introduce a simple clinical tuberculosis score together with a rapid urine test for the disease; introduce tuberculosis culture and drug-resistance tests
Insufficient hepatitis screening	No hepatitis treatment due to low sensitivity of rapid tests for hepatitis B and C viruses12	Increase awareness of the limitations of rapid tests

ART: antiretroviral therapy; CD4: cluster of differentiation 4; HIV: human immunodeficiency virus; RNA: ribonucleic acid.

Subsequently, awareness of these problems led to additional collaborative research projects between local HIV physicians and international researchers that aimed to explore possible solutions. In addition, the collaborations have encouraged local physicians to start their own research projects to find possible solutions to problems at the clinic. As a result, courses on good clinical practice, good laboratory practice and data management have been implemented and staff have taken part in English language lessons. Throughout, it was important to ensure that training for local staff was individualized. Furthermore, the synergies inherent in the rich spectrum of parties involved in research meant that knowledge and insights were multiplied.

Discussion

The largest HIV clinic in Guinea-Bissau faced numerous obstacles in delivering ART at a sufficiently high quality and, as a result, patients’ lives were put in jeopardy. These difficulties may have been exacerbated by the frequent recurrence of political instability in the country. If similar issues are faced by the many ART facilities in Africa that report few data, it is likely that the implementation of ART in affected areas will be impaired. Moreover, there will also be a risk of publication bias since the clinics discussed in scientific publications may not be representative of the real situation in many areas. Previous studies have shown that there is little collaboration between researchers within developing areas and that most research on HIV is carried out in the developed world. Consequently, it is increasingly recognized that international collaborative research is important for tackling global public health problems. In particular, international partnerships, especially those between developed and developing nations, are necessary in the fight against diseases that are endemic in, or disproportionably affect, the developing world. As summarized in Box 1: (i) we identified a range of persistent problems affecting ART delivery in Guinea-Bissau that involved drug supply, patient retention and inadequate laboratory facilities; (ii) we believe that underreporting of experience with ART in similar clinics in Africa may lead to publication bias; and (iii) we observed that international collaboration is important for identifying health-care problems and devising solutions.

In Guinea-Bissau, there were substantial, persistent problems with the delivery of ART, due to inadequate drug supplies, loss of patients to follow-up and inadequate laboratory services.

The occurrence of similar problems at the many ART facilities in Africa that report few data could impede the implementation of ART and result in publication bias.

International research collaborations between high- and low-resource settings can help identify problems, find solutions and enhance the capacity of health-care systems to manage HIV infection.

Partnerships between academic institutions in developed and developing countries is important for the delivery of health care as well as for research and training. Fortunately, the size and range of such partnerships have increased recently. The Swiss Commission for Research Partnerships with Developing Countries has developed A Guide for Transboundary Research Partnerships as an aid to the establishment of academic partnerships with developing countries. Also, Guinea-Bissau has taken part in international collaborations for many years through the INDEPTH network.

Our experience demonstrates that collaboration between physicians in high- and low-resource settings and between clinicians and researchers can help solve everyday clinical problems and enhance the capacity of the health-care system. Consequently, we believe that international research collaboration can help improve the effectiveness of ART in low-income countries and can benefit both partners. One unique facet of the collaboration in Guinea-Bissau was that researchers from developed countries lived in Guinea-Bissau and, as a result, developed a clear understanding of the problems faced in daily practice. In addition, the fact that we were able to follow up the large number of subjects in our HIV cohort for seven years despite difficult working conditions indicates that collaboration can be sustainable. An increasing number of scientific publications have resulted and it is hoped that additional funding for the cohort study group will further improve the capacity of the health-care system.

In conclusion, the management of people with HIV infection in vulnerable countries is still very challenging. However, international research collaboration can help identify problems and solutions, as well as enhance the capacity of the health-care system. Future research by the Bissau HIV cohort study group will demonstrate whether our identification of problems with the delivery of ART has led to measurable benefits, such as fewer patients being lost to follow-up, lower mortality, better diagnosis of opportunistic infection, more frequent detection of treatment failure and better-educated local staff.