Causes of death in the human immunodeficiency virus population in Western Jamaica

Background: Monitoring the causes of death in patients with human immunodeficiency virus (HIV) in the era of expanding access to antiretroviral therapy in resource-limited settings has implications as more deaths are reported for reasons other than AIDS. Aims: To determine the causes of mortality in HIV-infected adults in Western Jamaica. Materials and Methods: Patients with HIV infection with a death certificate with a known cause of death between 2005 and 2010 were reviewed. Results: There were 189 patients. Co-morbidities were present in 25.3%. The mean age at death was 42.4 years. Early disease (World Health Organization [WHO] stages 1 or 2) was the presentation in 21.5% while 78.6% presented with advanced disease (WHO stages 3 or 4). The mean CD4 count at diagnosis was 95 cells/mm ³ . In patients presenting with early disease, 14.2% presented with sexually transmitted infections, 22.8% skin manifestations, and 14.2% lymphadenopathy. In patients presenting with late disease, 41.7% had Pneumocystis jirovecii pneumonia (PCP), 18.9% central nervous system (CNS) toxoplasmosis, 11.3% HIV-associated nephropathy, and 5% cryptococcal meningitis. At death, 72.6% were in WHO class 4, and 21.2% class 3. The average CD4 count at death was 75.5 cells/mm ³ . Overall, 55.2% of the patients had received highly active antiretroviral therapy. PCP accounted for 42.9% of deaths, 27.3% had CNS opportunistic infections, HIV nephropathy 16.4%, and 4.6% had malignancies. About 52.3% of patients died within 1 year of diagnosis with HIV, while 68.3% died within 2 years. Conclusion: Patients with HIV are presenting with late disease and dying of conditions that are AIDS-related. Efforts to improve early diagnosis and treatment are urgently needed in Jamaica.

Keywords: CD4, human immunodeficiency virus, mortality

Before the introduction of highly active antiretroviral therapy (HAART), the major causes of death of human immunodeficiency virus (HIV) infected patients were AIDS-defining events. Studies on the causes of death conducted in several countries before 1997 reported that AIDS-defining events contributed to about 85% of fatalities among HIV-infected patients. ^{[1],[2],[3],[4]} However, since 1997, when HAART was largely introduced in routine case management, mortality decreased dramatically among HIV-infected patients.

There are increasing numbers of deaths of HIV-infected individuals that are being reported for causes other than AIDS, such as hepatitis B and C viral infection, cardiovascular disease, and malignancies. ^{[5],[6],[7],[8]} However, AIDS-related deaths are still being reported for diverse reasons, including failure of or late access to care, antiretroviral drug toxicities and failure of HAART secondary to drug-resistant virus or advanced disease. ^{[9],[10],[11],[12]}

Continued research into various aspects of HIV/AIDS, including its varying clinical manifestations and causes of mortality is needed for better understanding of this disease. The causes of mortality needs to be monitored and investigated in order to identify emerging causes of death and to improve the epidemiological surveillance and case management of HIV-infected patients in the era of HAART.

The overall prevalence rate of HIV in Jamaica is approximately 1.7%. ^[13],[14] Since the advent of free access to HAART in 2004, death rates in Jamaica have declined from 514 reported HIV-related deaths in 2005 to 333 in 2010. The present study determined the mortality of HIV-infected adults at the Cornwall Regional Hospital (CRH) in Western Jamaica during the 6-year period of 2005-2010.

All patients with HIV infection who died in the 6-year period between January 1 ^st , 2005 and December 31 ^st , 2010 at the CRH in Western Jamaica were studied. The study population comprised patients over the age of 13 years, who had a diagnosis of HIV and had a recorded death certificate generated at CRH and had a known underlying cause of death.

Medical records were reviewed for all deaths within the study period with a death certificate registering and coding HIV among the diagnoses at CRH. The primary outcome was the immediate, underlying causes of death taking into account morbidity at the time of death. Demographic and clinical data for the study population were obtained and classified patients based on their initial clinical presentation and at the time of death using the World Health Organization (WHO) Staging of HIV/AIDS into stages 1-4. ^[15] Patients were grouped according to the year of HIV diagnosis into two periods: Before 2004 (preHAART) and 2004-2010 (postHAART). The use of HAART, compliance with HAART and compliance with clinic visits were assessed. Compliance was self-reported with the definition of compliance being reports of compliance on medications of >95%, partially compliant between 80% and 95% and noncompliance <80%. Compliance with clinic visits was defined as complete compliance at 100% clinic visits. Partial compliance indicated attendance at 80-99% of clinic visits and noncompliance attendance at <80% of clinic visits. Death certificates were reviewed, and underlying causes of death analyzed. Persons with an unknown underlying cause of death were excluded from the analysis.

The study was approved by the Ethics Committee of the Western Regional Health Authority, Ministry of Health, Jamaica.

Statistical analysis was performed using SPSS 10.0 statistical software (SPSS, Chicago, IL, USA).

There were 189 patients who had a diagnosis of HIV, who died between January 1 ^st , 2005 and December 31 ^st , 2010. The mean age was 40.9 years. The male to female ratio was 3:2. The majority of the patients (84.4%) were diagnosed with HIV in the time period 2004-2010. Co-morbidities were present in 25.3% with hypertension being the most common occurring in 43.7% in those with co-morbidities.

At presentation, 21.5% (35/163) had early disease (WHO stages 1 or 2) while 78.6% (128/163) presented with advanced disease. Of those with advanced disease 30.1% were in WHO stage 3 and 48.5% WHO stage 4. The mean CD4 count at diagnosis was 95 cells/mm ³ and 28.3% (13/45) had a CD4 >200 cells/mm ³ at diagnosis.

The clinical presentations varied with conditions associated with HIV and/or AIDS and presentations that were nonHIV/AIDS related. In addition, several patients had both types of presentations. Of patients who presented with early disease (WHO stages 1 and 2), 14.2% (5/35) presented with sexually transmitted infections, 22.8% with skin manifestations, and 14.2% with lymphadenopathy. Of those who presented with late disease (WHO stage 4), 41.7% (33/79) had Pneumocystis jirovecii pneumonia (PCP), 18.9% had central nervous system (CNS) toxoplasmosis, 11.3% had HIV-associated nephropathy (HIVAN), and 5% had cryptococcal meningitis [Table 1]. Of the clinical presentations that were AIDS-related, PCP was the most common presentation (32.35%), followed by CNS toxoplasmosis (17.6%), generalized lymphadenopathy (14.7%), candidiasis (10.7%), and HIV-nephropathy (9.8%).

The most common clinical presentation that were not AIDS-related were dermatological manifestations (14.3%), lower respiratory tract infection (14.3%), constitutional symptoms (11.2%), and gastrointestinal manifestations (8.1%).

The average age at the time of death was 42.4 years. The majority of the patients were in WHO category III and IV at death, 21.2% had a WHO class III while 72.6% were WHO class IV. In contrast, 5.6% of patients were WHO class I at the time of death and 0.6% WHO class II [Table 2]. The average CD4 count at death was 75.5 cells/mm ³ . Only 4.7% (7/149) of patients had a CD4 count of >200 cells/mm ³ at the time of death.

The cause of death was most frequently PCP which accounted for 42.9% (53/128) of deaths, followed by CNS opportunistic infections, 27.3%, of which 23.4% had CNS toxoplasmosis. HIVAN accounted for 16.4% of deaths while malignancies accounted for 4.6% of which 57.1% had B cell lymphomas. Of the causes of death that were not AIDS related, lower respiratory tract infections accounted for 24.1% of deaths [Table 3].

Of the HIV-related deaths, 52.3% of patients died within 1 year of being diagnosed with HIV infection while 68.3% died within 2 years. Of the nonHIV-related deaths, 56.4% occurred within 1 year of the diagnosis. 79.3% of nonHIV-related deaths occurred in patients who were diagnosed with HIV in the time interval 2004-2010 which was similar in HIV-related deaths where 86.7% of patients who died were diagnosed with HIV in the same time interval. Patients presenting with an HIV-related illness were more likely to have an HIV-related cause of death, with 65% of patients dying of an AIDS-related cause of death had an HIV-related clinical presentation at the time of diagnosis (P < 0.01).

Highly active antiretroviral therapy was given to 55.2%, 45.2% of these patients were compliant, 19% partially compliant and 35.7% were noncompliant. Of patients not receiving HAART (44.8%), 67.9% (53/78) died in the same year as diagnosis. Of the HIV-related deaths, 54.8% of the patients were on HAART. Similarly in the nonHIV-related deaths 56.1% of patients were on HAART. There was no statistical significance in the cause of death based on HAART administration (P = 0.8). Of patients who died within 1 year of diagnosis, 44.2% of patients were on HAART and 55.8% of patients were not (P = 0.01). Patients receiving HAART were also more likely to live longer (P = 0.01). Of the patients that were receiving therapy, 58.8% had no change in their clinical stage between presentation and death but 35% had a decline in their WHO clinical stage despite antiretroviral therapy.

The Caribbean has a relatively high-prevalence of HIV infection with national prevalence rates surpassing 1%. ^[14] The epidemic however appears to have stabilized in Jamaica, with a national adult HIV prevalence of 1.6% over the last few years. ^[13] HAART became widely available across Jamaica in 2004. The CRH is one of three tertiary referral centers in Jamaica. Patients with HIV or AIDS may be managed in hospital or seen in the outpatient HIV clinic with a patient registry of about 1000 patients. In the Parish of St. James in Western Jamaica, the 2011 national data quoted a prevalence rate of 2094.6 HIV/AIDS cases per 100,000 population, which is the highest in the country. ^[16]

Accurate estimates of mortality are necessary for HIV surveillance, including assessments of antiretroviral treatment programs. ^[17] In the present study, patients with HIV presented with advanced disease, low CD4 counts and late in the course of the spectrum of HIV disease. A recent study from Jamaica indicate that the presence and number of symptoms were directly associated with the CD4 count. ^[18] Opportunistic infections continue to cause significant morbidity and mortality in the HIV-patient population in Jamaica. A previous survey reported a rate of 4.7% of cases diagnosed with an opportunistic infection. In this study, many patients presented with opportunistic infections indicating that the diagnosis of HIV were made when patients have advanced disease. The study also highlighted a low CD4 counts at presentation. ^[19]

Most patients in this study were diagnosed with HIV when HAART was widely available in Jamaica. Although antiretroviral medications were given to 55.2 % of patients, compliance was relatively low at 45.2 %. The WHO category at the time of death in the majority of cases was that of late disease with low CD4 counts. The majority of patients were dying less than a year after the diagnosis of HIV was made and the WHO staging for most patients was largely unchanged despite medication and in approximately one third of patients there was an actual decline in WHO staging. The causes of death were largely pulmonary and CNS opportunistic infections which can be prevented with prophylactic medications. In a comparison of treatment outcome between poor and high-income countries, patients starting HAART in resource-poor settings had increased mortality rates in the 1 ^st months on therapy, compared with those in developed countries. The higher mortality in low-income countries during the 1 ^st months of treatment was partly explained by the lower CD4 cell counts and more advanced clinical stage. ^[20]

AIDS-defining illnesses continue to be a major cause of mortality in the HAART era in populations where access to care and adherence to HAART is limited. ^[21] In a study in Europe, despite HAART, the main underlying causes of death were AIDS related in 47%, in part due to late diagnosis. ^[22] In a report from the USA, PCP remained an important cause of death in the HAART era, possibly because more than 50% of HIV-infected patients who died were not receiving HAART. In Western Canada, even in a setting where all health care is provided free of charge by the state, high HIV/AIDS death rates persist because of the lack of, or only marginal access to, antiretrovirals. Among those who accessed treatment, fewer than half received consistent treatment before death. ^[12]

In other studies, the increasing use of HAART has altered the course of AIDS-related illnesses and has improved the quality of life in patients with HIV infection and has changed the causes of death in patients with AIDS. This was shown in a study from New York City, which revealed that the overall mortality declined, and the number of deaths due to sepsis and opportunistic infections declined with the use of HAART. ^[23] In a retrospective study in France, there was a general decrease in mortality and AIDS-related deaths were no longer the main cause of death with the use of HAART. Patients dying from AIDS-related events were more often female and had lower CD4 count, a higher level of HIV-RNA. ^[24] In Barbados, the HIV-specific death rates declined significantly since the introduction of HAART, but HIV infection continues to contribute to the premature deaths among adults, mainly because of the late presentation. ^[25]

Although HAART may lengthen the time to death in the present study, the causes of death were largely AIDS-related in those receiving antiretroviral therapy as well as those not receiving antiretroviral therapy. This may be due to other factors such as poor compliance with medications, late recognition of antiretroviral failure and immune reconstitution inflammatory syndrome for early opportunistic infection death. There is a persistence of HIV-related deaths that may be preventable in our setting compared to the changing epidemiology in developed countries where nonHIV-related deaths in people living with HIV/AIDS are increasing in number. Even in regions where HAART is currently available, the distribution of the causes of death may vary considerably between countries. ^[22] Achieving reductions in HIV-related deaths may require steps for earlier diagnosis of patients and initiation of antiretroviral agents, improved compliance with medications as well as compliance with follow-up and early recognition and early action in patients with immunological and/ or clinical failure on antiretroviral therapy. In Jamaica, improved strategies for detecting HIV infection before AIDS-defining complications develop are needed in the era of HAART through expanded access to improved screening programs. There is also a need for a more supportive environment for HIV patients and more comprehensive HIV policies and wider access to ARV treatment with better adherence support. ^[14]

There were several limitations in the present study. Physician’s death reports may underreport mortality among individuals on HAART and may underestimate HIV-related mortality. ^[17] Therefore, reviewing cause of mortality using death certificates may be imperfect. Furthermore, clinical and laboratory data was sometimes unavailable in patient records.

Late presentation and AIDS-related mortality continue to be prominent characteristics of the HIV epidemic in Jamaica. Efforts to improve early diagnosis and treatment and compliance with therapy and follow-up are urgently needed.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.145006

[Table 1], [Table 2], [Table 3]