Study of Patients Diagnosed With Advanced HIV in the HAART Era – OMEGA Cohort

Summary: Our objective is to analyse patients diagnosed with late- stage HIV infection in the highly active antiretroviral therapy (HAART) area. A prospective, observational study of all patients with an initial CD4<50 10^sup 6^/L was carried out. Epidemiological, clinical and HAART-associated data were analysed. Survival rates were estimated and pairs of survival curves were compared. The statistical program used was SPSS (version 10). In all, 349 HIV-infected patients were diagnosed, 117 (33.5%) had late- stage disease, mean CD4 23.9 10^sup 6^/L and mean viral load (VL) 5.38 log^sub 10^. In 98 men, mean age 39.5 years, percentage of AIDS cases at their first attendance was 83.8%. The median follow-up period was 28 months and 27 died. Pneumocystis carinii was the most frequent cause of AIDS (24.4%) and death (18.5%). Survival rates at 12, 24 and 36 months were 95.6%, 85.8% and 72.4%. HAART was started in 82.1%. VLs <50copies/mL at one, two and three years of treatment were 55.2%, 55.7%) and 58.0%. Resource utilization included 0.58 hospitalization/patient/ year and 0.07 events/patient/year. HAART- related complications were as follows: 50% lipodystrophy, 9.7% hypertension, 22.2% hyperglycaemia, 26.4% hypercholesterolaemia, 31.9% hypertrygliceridaemia and 18.1% mixed hyperlipaemia. Over one- third of our patients have advanced HIV infection at diagnosis. However, the outcome is favourable, with a good immunovirological response and few new opportunistic events. HAART-related complications were frequent.

Keywords: advanced HIV infection, HAART, cohort study, survival

Introduction

Highly active antiretroviral therapy (HAART) has changed the prognosis for HIV patients, with marked reductions in morbidity and mortality.1″3 The CD4 lymphocyte count is a prognostic factor in patients starting HAART, with important differences in those who initiate therapy with a count below 50 CD4 lymphocytes 10^sup 6^/ L.4’5 Early diagnosis therefore, besides being necessary, has other advantages such as reduced transmission rates, preservation of the immune system and prolongation of the period free of disease or opportunistic events.6 Despite these potential benefits, a high number of new cases of HIV infection are not diagnosed until they already have advanced disease with a low CD4 lymphocyte count.7″9 This occurs not only in our area but also elsewhere and has remained the case for several years.10’11

We report the results from the OMEGA Cohort, composed of subjects from one single hospital with already severe immunosuppression at the time of HIV diagnosis in the era of HAART. Epidemiological and clinical characteristics, response to HAART, their associated complications, survival and number of hospital visits were analysed.

Methods

This prospective, observational study included all patients diagnosed with HIV infection in our Unit from January 1997 to June 2003 with an initial CD4 lymphocyte count below 50 10^sup 6^/L (OMEGA Cohort). We analysed epidemiological and clinical characteristics, as well as course of disease, treatment response and associated metabolic disorders. Estimations were made of the likelihood of death and deaths from all causes. We used the clinical part of the 1993 Centers for Disease Control and Prevention revision of the definition of an AIDS case (i.e. persons without an AIDS- defining illness were not classified as having AIDS).12 HAART was defined as antiretroviral therapy with a combination of at least three drugs, including nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). In all analyses, we used an intention-to- continue-treatment (ITT) approach and thus ignored subsequent changes in treatment, including treatment interruptions and terminations.

The presence of lipodystrophy syndrome was defined according to the modified criteria of Carr et ni.13 Fat accumulation or loss was scored for the neck, abdomen, parotid glands, breasts, legs, arms, face and buttocks on a scale of 0-3 according to severity (O absent, 1 mild, 2 moderate, 3 severe). The final score was the sum of the individual scores for each body region and this was used to define the degree of lipodystrophy. Dyslipidaemia, diabetes mellitus and hypertension were diagnosed according to international criteria.14″16 Participants were followed up until 30 June 2003; those lost to follow-up were censored on the date of the last known contact with our clinic and for mortality on the date of death. Cumulative mortality rates were estimated using Kaplan-Meier methods. The logrank test was then used to compare pairs of survival curves. Time from diagnosis of HIV infection was measured in months. Data were analysed with SPSS (version 10). All significance tests were two-tailed and a P value less than 0.05 was considered statistically significant.

Results

A total of 349 new patients were diagnosed with HIV during the study period, of whom 117 (33.5%) had advanced disease. These 117 patients thus formed the study cohort. The epidemiological and clinical characteristics of these patients are shown in Table 1. The men were older than the women (40.7 versus 33.0 years; P < 0.001) and patients with a homosexual risk for HIV were also older compared to those with a risk associated with injection drug use (43.9 versus 34.0 years; P < 0.001). Pneumocystis carinii pneumonia (PCP) was the most common AIDS-defining disease (Table 2).

The median follow-up period of the cohort was 28 months; 23 patients were lost and 27 died, of whom 13 (48.1%) died within four weeks of diagnosis. PCP was the most common cause of death (18.5%). The Kaplan-Meier probabilities of survival at 12, 24 and 36 months were 79.3%, 75.7% and 74.2%, respectively (Figure 1).

HAART was initiated in 96 (82.1%) patients; 74.7% with two NRTI + one PI and 27.3% with two NRTI + one NNRTI. The median delay to starting HAART was one month (0-48). Viral load (VL) was undetectable by ITT (< 50 copies/mL) in 55.2% after one year, 56.6% after two years and 58% after three years. Patients who received PI and those who received no PI at any time had the same probability of survival (85.6% versus 86.4% after three years; P = 0.98; log rank). The increase in CD4 lymphocytes during the first year was similar in patients treated with PI and those treated with NNRTI (192 versus 171; P = 0.059).

Table 1 Epidemiological and clinical characteristics of the OMEGA Cohort

Table 2 Most common AIDS-defining diseases in the 98 patients with AIDS at diagnosis of HIV infection

Figure 1 Survival probability of the OMEGA cohort

There were 172 hospital admissions in 92 patients, with a mean stay of 18.2 days. This represents a rate of 0.58 admissions per patient per year and a stay of 7.2 days per patient per year. During follow-up, 18 new opportunistic events were diagnosed in 12 patients (0.07 events per patient per year).

Of those patients receiving treatment, with a median follow-up of 30 months, 50.0% had lipodystrophy, 9.7% hypertension, 22.2% hyperglycaemia, 26.4% hypercholesterolaemia, 31.9% hypertriglyceridaemia and 18.1% mixed hyperlipidaemia at the end of the study. There were no differences between patients treated with PI and those receiving NNRTI.

Discussion

The most notable result of this study was that onethird of all new cases of HIV infection were diagnosed at an advanced stage of the disease. Although the number of new diagnoses of HIV infection has fallen in our area over recent years,9 an important number of people still discover their HIV infection at a late stage and may therefore miss important treatment opportunities. Patients with a late diagnosis were somewhat older, but there were no differences in sex or HIV risk group, and the delay was seen throughout the study period.9 This finding is in line with recent data reported from various other settings7’8’17″20 and suggests that, although many causes may contribute, access to health care is not sufficient for early detection. Increasing effort should be made at several levels both to reduce the number of persons infected and to diagnose them as early as possible.6 Late diagnosis is not only associated with marginal patients and drug abusers.17’19 In our study, only about 10% had problems with illegal drugs at the time of HIV diagnosis and almost half had a stable partner. However, over 85% of patients with a late diagnosis had no education or only primary studies. Higher income and educational levels have already been associated with a history of earlier HIV diagnosis.17

Most patients had symptoms related to HIV infection and 84% had AIDS-defining opportunistic diseases. Indeed, this appears to be the general rule when diagnosis is so late.9″11’17″19 The opportunistic diseases were similar to those of other AIDS studies in this area.19 The most common were PCP and tuberculosis. Initial mortality during the first four weeks after diagnosis was high (10%), with PCP being the main cause of death. Most patients started HAART after a median delay of one month, and most followed a regimen with PI, though 25% were never given this group of drugs during the course of their disease. Despite intense immunosuppression and very high VLs, the treated patients responded very well; there was a notable increase in CD4 ly\mphocytes and the VL was undetectable in over half the patients after 48 weeks. In a recent report,21 the magnitude of the initial rise in CD4 T-cells after beginning antiretroviral therapy was determined by baseline HIV RNA levels, while long-term restoration of CD4 T cells was related to age. Other authors have suggested that therapy with PI might provide an additional immunological benefit over that directly related to its antiviral activity.22’23 The increase in CD4 lymphocytes in our series was similar in patients treated with PI and those receiving NNRTI. The likelihood of new opportunistic events once HAART is initiated is not very high, considering the baseline immunological status. During the first few months after diagnosis, our patients had an important number of prolonged hospital admissions because of opportunistic events associated with late diagnosis. However, the number of admissions and the length of stay were then much lower, due to the immunological improvements of patients on HAART. This, together with the stabilization of the likelihood of survival of the cohort after the first year, suggests that if a patient overcomes the first few months after diagnosis and starts HAART, the patient will reap all the benefits from this type of therapy.1″5

The good prognosis currently applicable to patients with HIV infection3″5 also applies to these severely immunosuppressed patients, after they survive their high initial risk of morbidity and mortality. However, they also have to pay the toll levied by chronic HAART.24 At the time of closing this study, with a median follow-up of more than 30 months, there is an important percentage of adverse side effects associated with HAART. Some, such as dyslipidaemia, insulin resistance or hypertension, are cardiovascular risk factors and we do not yet know whether at some time in future these patients will have more cardiovascular events than their counterparts in the general population.25

In summary, the OMEGA cohort studied herein represents a group of patients with a late diagnosis of HIV infection. This group formed an important number of all those newly diagnosed with HIV. With the generalization of HAART, these patients now have an excellent prognosis provided they survive the first few months, during which associated morbidity and mortality remain high.

Acknowledgements: The authors thank Mr Ian Johnstone for his help in translating the manuscript.

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(Accepted 20 January 2004)

J Santos MD PhD, R Palacios MD PhD, J Ruiz MD, M Gonzalez MD and M Marquez MD

Infectious Diseases Unit, Internal Medicine Service, Hospital Virgen de la Victoria, Campus Teatinus s/n, 29010 Malaga, Spain

Correspondence to: Dr Jess Santos Gonzlez

Email: med000854@saludalia.com

Copyright Royal Society of Medicine Press Ltd. Mar 2005