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Severe hyperlactataemia complicating antiretroviral therapy with stavudine first-line therapy in South Africa: incidence, risk factors and outcomes.

Symptomatic hyperlactataemia (SHL) and lactic acidosis (LA)result from mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitors (NRTIs) (especially stavudine (d4T) and didanosine (ddI)). High rates of these conditions are being reported in the SA public sector ART programme. We undertook this study to document the incidence, risk factors and outcomes of severe SHL (defined as serum lactate [greater than or equal to]5 mmol/l) at one referral facility in Cape Town, G F Jooste Hospital. We also assessed the safety of re-challenge with AZT (an NRTI that carries a lower risk for mitochondrial toxicity than d4T) in a select group of patients with less severe presentations. G F Jooste Hospital is a public sector hospital which serves a population of approximately 1.5 million people. There are 6 primary care ART clinics which refer to G F Jooste. There were two parts to the study. The first was a retrospective observational study on patients referred to G F Jooste Hospital with severe SHL. All patients with a lactate [greater than or equal to]5 mmol/l attributed to NRTIs during the period 1 August 2003 to 30 November 2005 were included. We calculated cumulative exposure to ART among patients attending the 6 ART clinics to derive an estimated rate of referral. Secondly, a matched case-control study which used incidence density sampling and was based on the cases sampled in the observational study outlined above was conducted. For practical reasons, controls were randomly selected from the same cohort (the same month commencing ART and at the same clinic--i.e. matched on facility and duration on ART) as each case.

MAJOR FINDINGS

OBSERVATIONAL STUDY

Seventy-three patients were diagnosed with severe SHL during the study period. During this period there was a cumulative exposure to ART of 7 080 patient years at all 6 ART clinics in the referral area, resulting in an estimated rate of referral for severe SHL of 10/1 000 years of treatment.

Sixty-nine patients (95%) were female. All 73 patients were on d4T-containing regimens, or had been switched off d4T in the preceding few weeks. The median duration on ART was 10 months (IQR = 8-11.3). The median serum lactate was 7.6 mmol/l. Thirteen patients (18%) had standard bicarbonate (SBC) [greater than or equal to] 20 mmol/l, 49 patients (67%) < 20 mmol/l (i.e. lactic acidosis), and in 11 (15%) SBC was not measured.

Eleven patients died acutely (15%), and 1 patient died 4 months later. SBC below 15 mmol/l was the only risk factor consistently associated with acute mortality in univariate and multivariate modelling (OR = 35, p = 0.004, adjusted for age).

MANAGEMENT AND OUTCOME

All patients were managed acutely according to a management guideline which included general supportive therapy, vitamin supplementation and treatment of complications. ART was immediately interrupted in 66 patients. In the other 7 patients d4T was switched to AZT and ART was not immediately interrupted. However, in 5 of these 7 patients there was continued clinical or biochemical deterioration necessitating ART interruption. Thus 71 patients in total interrupted ART.

Of the 62 initial survivors, 3 were lost to follow-up and 59 patients were re-established on safer ART regimens. These included the 2 successful switches, plus 57 patients rechallenged with safer ART regimens once lactate levels had normalised after a mean 87-day treatment interruption.

The outcomes of those re-established on ART were: 29 patients with less severe presentations (all these patients had lactates < 10.4 mmol/l and SBCs > 14 mmol/l and none had pancreatitis) were restarted on an ART regimen which contained AZT and 3TC, with lactate monitoring. One of these patients was lost to follow-up. The remaining 28 patients were still in care on the same regimen at the time of data censure, with no recurrence of hyperlactataemia. A cumulative follow-up of 1 137 weeks (mean = 39 weeks) was available on these patients without recurrence of SHL. The other 30 more severe cases were reinitiated on a tenofovir-containing regimen or an NRTI-sparing regimen (i.e. Kaletra + NNRTI). There were no recurrences among these patients.

MATCHED CASE-CONTROL STUDY

DEMOGRAPHIC AND CLINICAL FEATURES AT BASELINE ASSOCIATED WITH SUBSEQUENT SHL

In multivariate analysis, compared with people with a baseline weight below 60 kg, those between 60 and 74 kg were 5 times more likely to experience severe SHL (95% CI 1.6-15.4) while those over 75 kg had an increased 19-fold risk (95% CI 4.8-77.1). The odds ratio for females was 44.2, with a wide confidence interval due to the paucity of men in the study (95% CI 6.4-303.8).

CLINICAL VARIABLES ASSOCIATED WITH SHL DURING FOLLOW-UP

In a regression model, patients having at least one of the listed major symptoms (abdominal pain, diarrhoea, nausea, and vomiting) within 80 days prior to case presentation were 18 times (95% CI 3.5-97.6) more likely to present with severe SHL. Weight gain of [greater than or equal to] 6 kg in the first 3 months on ART was a further clinical association with severe SHL, with an odds ratio of 11 (95% CI 1.9-67.5). Patients with weight loss of [greater than or equal to] 3 kg during the last 3 months prior to diagnosis were 12 times (95% CI 2.2-62.1) more likely to present with severe SHL. Concurrent peripheral neuropathy was also found to be independently associated with developing severe SHL (OR 8.4, 95% CI 1.4-51.8).

WHAT ARE THE IMPLICATIONS FOR CLINICAL PRACTICE?

The rate of severe SHL (referral rate of 10/1 000 patient treatment years) was higher than that reported from many developed-world settings. This is likely due to uniform use of d4T in first-line therapy, but may also be related to the risk factor profile of patients starting ART in SA. In order to minimise the morbidity and mortality related to this condition it is important to develop strategies to address prevention, earlier diagnosis and appropriate management.

Preventive measures may include:

* Changes in drug regimens on a programme level: an example would be substituting d4T with tenofovir, a drug which has not by itself been associated with lactic acidosis.

* Dose reduction of d4T: the WHO now recommends d4T be dosed at 30 mg bd in all patients regardless of weight. This is anticipated to reduce mitochondrial toxicity rates.

* Strategies focusing on high-risk patients: our study identified female gender, higher weight and rapid weight gain after starting ART as risk factors for severe SHL. One strategy that has been advocated and is supported by these data is to start overweight women on AZT (or tenofovir) rather than d4T and to switch those who become overweight on ART from d4T to AZT (or tenofovir).

To facilitate early diagnosis it is essential that a high index of suspicion for SHL is maintained. Clearly those at highest risk (overweight women) should be monitored most closely. Our study shows that symptoms such as abdominal pain, diarrhoea, nausea, and vomiting, weight loss [greater than or equal to] 3kg as well as symptoms of neuropathy are important heralds of the condition. Also, most patients (85%) in this study presented with severe SHL after having been on ART for between 6 and 14 months. This period is thus the critical time to monitor for symptoms of SHL and weight loss.

Management of patients with severe SHL involved stopping drugs and a range of supportive measures. (1) It is worth noting that in 7 patients d4T was switched to AZT and ART was not immediately stopped. This strategy however failed with 5 of these patients deteriorating and requiring that ART be stopped. It is thus advisable that in all patients presenting with SHL and lactate > 5 mmol/l ART be immediately stopped.

Once ART was stopped it took a mean of 3 months for the lactate to normalise so that ART could be re-initiated. We were encouraged to find that our practice of re-challenging with an AZT-containing regimen in a group of 29 patients with less severe presentations (all had lactate < 10.4 mmol/l and SBC >14 mmol/l and none had pancreatitis) was well tolerated with no recurrences of SHL. Lactate levels and symptoms were closely monitored in these patients on rechallenge. This provides a Kaletra-sparing alternative, while we wait for tenofovir to be available in the public sector, for carefully selected patients who can be monitored on rechallenge.

REFERENCE

(1.) Southern African HIV Clinicians Society. Guidelines for the prevention, diagnosis and management of NRTJ-associated symptomatic hyperlactataemia and lactic acidosis. Southern African Journal of HIV Medicine 2006; Issue 22; 8-15.

Meg Osler (1,2), Dave Stead (3), Kevin Rebe (2,3), Andrew Boulle (1,2), Graeme Meintjes (2,3) (1) Department of Health, Provincial Government of the Western Cape, (2) University of Cape Town, (3) G F Jooste Hospital, Cape Town
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Article Details
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Title Annotation:ABSTRACTS: CRO1 2007
Author:Osler, Meg; Stead, Dave; Rebe, Kevin; Boulle, Andrew; Meintjes, Graeme
Publication:Southern African Journal of HIV Medicine
Article Type:Clinical report
Geographic Code:1USA
Date:Jun 1, 2007
Words:1471
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