Conceived and designed the experiments: LTM JG JH RTG DRB. Performed the experiments: LTM JH AE EC KA MCG. Analyzed the data: LTM MG AJG. Wrote the paper: LTM JG RTG DRB. Chart abstraction and data entry: LTM JH AE EC KA MCG.
The authors have declared that no competing interests exist.
Stavudine continues to be used in antiretroviral treatment (ART) regimens in many resource-limited settings. The use of zidovudine instead of stavudine in higher-risk patients to reduce the likelihood of lactic acidosis and hyperlactatemia (LAHL) has not been examined.
Antiretroviral-naïve, HIV-infected adults initiating ART between 2004 and 2007 were divided into cohorts of those initiated on stavudine- or zidovudine-containing therapy. We evaluated stavudine or zidovudine use, age, sex, body mass index (BMI), baseline CD4 cell count, creatinine, hemoglobin, alanine aminotransferase, and albumin as predictors of time to LAHL with Cox Proportional Hazards (PH) regression models.
Among 2062 patients contributing 2747 patient years (PY), the combined incidence of LAHL was 3.2/100 PY in those initiating stavudine- and 0.34/100 PY in those initiating zidovudine-containing ART (RR 9.26, 95% CI: 1.28–66.93). In multivariable Cox PH analysis, stavudine exposure (HR 14.31, 95% CI: 5.79–35.30), female sex (HR 3.41, 95% CI: 1.89–6.19), higher BMI (HR 3.21, 95% CI: 2.16–4.77), higher creatinine (1.63, 95% CI: 1.12–2.36), higher albumin (HR 1.04, 95% CI: 1.01–1.07), and lower CD4 cell count (HR 0.96, 95% CI: 0.92–1.0) at baseline were associated with higher LAHL rates. Among participants who started on stavudine, switching to zidovudine was associated with lower LAHL rates (HR 0.15, 95% CI: 0.06–0.35). Subgroup analysis limited to women with higher BMI≥25 kg/m2 initiated on stavudine also showed that switch to zidovudine was protective when controlling for other risk factors (HR 0.21, 95% CI .07–0.64).
Stavudine exposure, female sex, and higher BMI are strong, independent predictors for developing LAHL. Patients with risk factors for lactic acidosis have less LAHL while on zidovudine- rather than stavudine-containing ART. Switching patients from stavudine to zidovudine is protective. Countries continuing to use stavudine should avoid this drug in women and patients with higher BMI.
Lactic acidosis is a potentially fatal side effect of nucleoside analog reverse
transcriptase inhibitors (NRTIs)
Of the NRTIs, the dideoxynucleosides (stavudine and didanosine) confer the highest
risk of lactic acidosis
Observational studies suggest that specific risk factors associated with the
development of hyperlactatemia include female sex
Until April 2010, first-line therapy in South Africa included stavudine, lamivudine,
and either efavirenz or nevirapine. Based on observational findings from a
site-specific study that identified a high incidence of lactic acidosis in women
with BMI≥28 kg/m2, in August 2005 the HIV Clinic at McCord Hospital in
Durban, South Africa substituted zidovudine for stavudine in initial ART for
patients with these two risk factors
To evaluate the impact of risk factor-guided selection of initial therapy, we compared the combined incidence of lactic acidosis and hyperlactatemia among treatment-naive patients initiating stavudine-containing therapy with those starting zidovudine-containing therapy. We hypothesized that risk-factor-guided ART (initiating women with BMI≥28 kg/m2 on zidovudine rather than stavudine) would be associated with decreased incidence of lactic acidosis and hyperlactatemia. We also assessed predictors of lactic acidosis and hyperlactatemia.
Ethics approvals were obtained from the McCord Hospital Medical Ethics Research Committee and from the Partners Healthcare Institutional Review Board (Boston, MA). Given the nature of the study (retrospective chart review), the requirement for informed consent was waived by the ethics committees.
Patient data were collected from the outpatient HIV clinic at McCord Hospital in Durban, South Africa which has initiated over 8000 patients on ART. During the study period, initial ART included two NRTIs and one NNRTI: stavudine (30 mg twice daily; 40 mg twice daily if weight >60 kg) or zidovudine plus lamivudine and either efavirenz or nevirapine.
The study population included antiretroviral (ARV)-naïve, HIV-infected adults (age ≥18 years) with baseline laboratory data and at least one follow-up visit after ART initiation. Two retrospective cohorts were identified. The first cohort included patients who initiated stavudine-containing therapy between July 2004 and March 2007. The second cohort included patients who initiated zidovudine-containing ART between July 2004 and March 2007. Both cohorts included patients who initiated ART between August 2005 and March 2007 when the clinic made women with BMI≥28 kg/m2 eligible for initiation of zidovudine -containing therapy or for regimen switch from stavudine to zidovudine.
The primary outcome was event-free survival defined as the time from treatment
initiation to development of lactic acidosis (symptomatic or asymptomatic) or
hyperlactatemia (symptomatic or asymptomatic) (
Asymptomatic lactic acidosis | Symptomatic lactic acidosis | Asymptomatic hyperlactatemia | Symptomatic hyperlactatemia | |
Lactate (mmol/L) | ≥4.4 | ≥4.4 | ≥4.4 | ≥4.4 |
Abnormal values required | ≥2 | ≥1 | ≥2 | ≥1 |
Acidosis |
+ | + | − | − |
Symptoms |
− | + | − | + |
Based on AACTG criteria
Bicarbonate <20 mmol/L or pH<7.35.
New or otherwise unexplained symptoms of nausea or vomiting, abdominal pain or discomfort, abdominal distention, increased hepatic transaminases, unexplained fatigue, dyspnea, weight loss (≥5%), or muscle weakness.
Blood was drawn for lactate levels without use of a tourniquet and specimens were
transported on ice and processed within four hours (Beckman Coulter, Synchron
systems, California, USA). A handheld lactate detection device, a reliable proxy
for serum samples, was introduced in 2006 (Accutrend model #3012522)
Outcomes were classified from a review of the medical records of patients initiating ART during the study period. This review was facilitated by the requirement that clinicians record the reason for any change or discontinuation in ARV regimen from an electronic pull down menu. For patients who had a regimen change noted in the electronic record, paper charts were reviewed for the following: 1) documentation of a regimen change due to lactic acidosis; 2) documentation of a regimen change and signs or symptoms that could be consistent with lactic acidosis or hyperlactatemia (nausea, vomiting, abdominal discomfort, bloating, increased hepatic transaminases, fatigue, dyspnea, weight loss, muscle weakness); 3) documentation of a regimen change without specific reason listed; 4) death. Serum lactate test results for all study patients were reviewed. A lactate value above 3 mmol/L prompted review of the medical record for symptoms of hyperlactatemia, all available lactate values, other possible causes for symptoms or elevated lactate levels, and clinical outcome. Data were abstracted using standardized abstraction forms (LM, AE, JH). For a subset of patients (n = 20), two physicians carried out the abstractions with 100% agreement on outcome classification (JH, LM). Cases with unclear outcomes were adjudicated by a senior clinician (RG).
We also identified patients for whom clinicians had changed ART due to peripheral neuropathy, lipodystrophy, high BMI, and drug resistance, as indicated in the electronic medical record. We identified patients with regimen switch for clinical suspicion of LA or HL but who did not meet criteria. These subjects were not censored at change in regimen but followed out to a total two years of follow-up from treatment initiation. In addition, we identified subjects who changed clinic site, stopped ART, died or were lost to follow up.
Covariates were obtained from paper chart abstractions and included weight at treatment initiation (within 3 months) and height. Weights obtained during pregnancy were excluded. BMI was calculated (kg/m2) for all subjects in whom height and baseline weight were available. Sex, date of birth and baseline (the last value prior to ART initiation, or within 2 weeks) CD4 count, creatinine, hemoglobin, alanine aminotransferase, and albumin were extracted from the electronic record or the paper chart. All specimens were processed using standardized methods at laboratories in Durban.
The primary outcome was 2-year event-free survival (EFS) defined as the time from treatment initiation up to development of lactic acidosis or hyperlactatemia. Patients were also censored for loss to follow-up, change in clinic site, termination of treatment, death, or at study end. All others were followed for two years or until the primary outcome. Time on stavudine and zidovudine was calculated from start and stop dates entered by clinicians in the medical record.
We calculated crude incidence rates for the combined primary outcome (LAHL), the
combined incidence of peripheral neuropathy and lipodystrophy, death, and
loss-to-follow-up. Confidence intervals for event rates based on initial therapy
with stavudine or zidovudine were estimated using methods for exact binomial
confidence intervals and compared using Chi-square tests
Two-thousand-sixty-two patients contributing 2747 person years of follow-up were included in the study. The median age was 34.7 years (IQR 29.8, 40.6) and 60% were women. Eighty-nine percent initiated therapy with a stavudine-containing regimen. One-hundred sixty one (77%) of those who were initiated on a zidovudine-containing regimen were started because of higher BMI or other perceived lactic acidosis risk factors. The remaining patients were initiated on zidovudine because of pre-existing lipodystrophy (<1%), peripheral neuropathy (<1%), pregnancy (10%), or unknown reason (10%).
Median CD4 count at entry was 80 cells/mm3 (IQR 29–142). Median BMI for
subjects with complete data (88% had documented weight at entry,
76% had documented height) was 22 kg/m2 (IQR 20, 26). Compared with those
initiated on a stavudine-containing regimen, patients started on zidovudine were
older, more likely to be female, had a higher BMI, higher CD4 cell count, higher
albumin and higher hemoglobin. Other characteristics are described in
Initial ART includes: | |||
Variable | Stavudine | Zidovudine | p-value |
Number (patient years follow-up) | 1853 (2460) | 209 (287) | |
Age, years |
35.7 (8.3) | 37.8 (9.6) | <.001 |
Patient years of follow up |
1.3 (0.7) | 1.4 (0.6) | <.001 |
Female |
1078 (58.2) | 188 (90) | <.001 |
BMI (kg/m2) |
22 (19, 24) | 30 (28, 33) | <.001 |
CD4 (cells/mm3) |
75 (27, 138) | 129 (61, 172) | <.001 |
Creatinine (mg/dL) |
1.0 (0.4) | 0.9 (0.3) | .21 |
ALT (IU/L) |
24 (18, 35) | 23 (17, 32) | .27 |
Albumin (g/L) |
31.2 (7.3) | 34.9 (5.3) | <.001 |
Hemoglobin (g/dL) |
10.8 (2.1) | 11.6 (1.3) | <.001 |
Chi-square test was used for categorical variables, T-test for continuous where mean and standard deviation reported, and Wilcoxon rank sum where median and IQR reported.
In intention to treat analysis, combined incidence of LAHL was 3.2/100 PY in the
stavudine- and 0.34/100 PY in the zidovudine-initiated group (RR 9.26,
95% CI 1.28–66.93, p = .007). There were 36
lactic acidosis and 43 hyperlactatemia events in the stavudine group. In
contrast, there was 1 lactic acidosis event in the zidovudine group: this
occurred in a woman who initiated zidovudine-based therapy because of high BMI
(31 kg/m2); one year later, she was switched to stavudine because of anemia;
after eight months on stavudine-containing ART, she was diagnosed with lactic
acidosis. Mortality due to causes other than LAHL was 8.3% and
2.8% in stavudine- and zidovudine-initiated patients, respectively
(RR = 2.89, 95% CI:1.45–5.78,
p = 0.001). The combined incidence of physician-reported
peripheral neuropathy and lipodystrophy was 16.8/100 PY in stavudine- and
0.34/100 PY in zidovudine-initiated groups (RR = 59.84,
95% CI: 8.36–428.12, p<0.001). Loss to follow-up was equivalent
between the two groups (RR = 1.42, 95% CI:
0.68–2.96, p = 0.35). (
Initial ART includes: | ||||
Outcome | Stavudine (Incidence/100 PY) | Zidovudine (Incidence/100 PY) | Relative Risk Ratio [95% CI] | Chi-Square p-value |
Lactic acidosis or hyperlactatemia |
79 (3.2) | 1 (0.3) | 9.26 [1.28, 66.93] | .007 |
Mortality due to cause other than LAHL | 205 (8.3) | 8(2.8) | 2.89 [1.45, 5.78] | .001 |
Peripheral neuropathy or lipodystrophy |
414 (16.8) | 1 (0.3) | 59.84 [8.36, 428.12] | <.001 |
Loss to follow-up | 99 (4.0) | 8 (2.8) | 1.42 [0.68, 2.96] | .35 |
Primary endpoint: 37 lactic acidosis, 43 hyperlactatemia.
As indicated by clinician report in the medical record.
In univariate Cox proportional hazards analysis, stavudine in the initial
treatment regimen, female sex, higher BMI, and higher baseline albumin were each
associated with increased risk of LAHL (
Variable | Hazards Ratio [95% CI] | p-value | Adjusted Hazards Ratio [95% CI] | p-value |
Age (years) | 1.02 [0.99, 1.04] | .14 | – | .22 |
Female sex | 2.22 [1.31, 3.75] | .003 |
|
|
BMI in first year (30% change kg/m2) | 1.53 [1.10, 2.12] | .01 |
|
|
BMI after first year (30% change kg/m2) | 0.76 [0.44, 1.32] | .33 | – | .55 |
Stavudine use | 5.81 [2.52, 13.43] | <.0001 |
|
|
Initial CD4 count (10 cells/mm3) | 0.99 [0.96, 1.03] | .80 |
|
|
Initial Albumin (g/L) | 1.04 [1.01, 1.07] | .004 |
|
|
Initial Creatinine (mg/dL) | 1.00 [0.99, 1.01] | .09 |
|
|
Initial ALT (IU/L) | 1.00 [0.99, 1.01] | .38 | – | – |
Hemoglobin (g/dL) | 1.07 [0.95, 1.19] | .26 | – | – |
Multivariate model with 80 events, 1546 subjects with complete data for all variables.
In multivariable Cox PH regression to assess predictors of event-free survival,
hemoglobin and ALT were removed but age and CD4 cell count were included because
prior data and
Initial ART includes: | |||
Variable | Stavudine | Zidovudine | p-value |
Number (patient years follow-up) | 194 (274) | 132 (190) | |
Age (years) |
36 (7) | 38 (9) | .03 |
Patient years of follow up |
1.4 (0.6) | 1.4 (0.6) | .64 |
BMI (kg/m2) |
27 (26, 30) | 30 (29, 34) | <.0001 |
CD4 (cells/mm3) |
99 (64) | 122 (58) | .0003 |
Creatinine (mg/dL) |
0.85 (0.77, 0.94) | 0.88 (0.80, 0.98) | .02 |
ALT (IU/L) |
22 (17, 32) | 22 (17, 30) | .97 |
Albumin (g/L) |
32 (6) | 36 (4) | <.0001 |
Hemoglobin (g/dL) |
11.1 (1.7) | 11.7 (1.1) | .0001 |
T-test for continuous where mean and standard deviation reported, and Wilcoxon rank sum where median and IQR reported.
Women with BMI greater than or equal to 25 kg/m2 comprised 326 patients with 434
years of follow-up. The 194 women initiated on stavudine were younger; with
lower BMI, baseline CD4 cell count, creatinine, albumin, and hemoglobin compared
with 132 women initiated on zidovudine (
Variable | Adjusted Hazards Ratio [95% CI] | p-value |
BMI (30% change kg/m2) |
|
|
Stavudine use |
|
|
Initial CD4 (10 cells/mm3) | – | 0.99 |
Initial Albumin (g/L) | 1.01 [0.94, 1.08] | 0.83 |
Initial Creatinine (mg/dL) |
|
|
Multivariate model with 20 events, 298 subjects with complete data for all variables.
Of the 194 women with higher BMI who initiated stavudine-inclusive therapy, 137 were switched to zidovudine for reasons other than LAHL. Baseline characteristics (age, BMI, CD4 cell count, creatinine albumin, ALT, hemoglobin) were not significantly different from women with higher BMI initiated on stavudine-treatment who did not switch treatment arms. Women were switched for high BMI (79, 56%); lipodystrophy, peripheral neuropathy, or these plus elevated BMI (47, 34%); lab values and/or symptoms suggestive of hyperlactatemia that did not meet criteria for LAHL (7, 5%); and the remainder were switched for anemia, pregnancy, rash or other reasons. These participants subsequently contributed an additional 131.7 woman-years of follow-up (mean 1.1 years ±0.5) during which there were 5 LAHL events (3.8/100 woman years). All but one event occurred within 2–8 weeks of switching off stavudine after an average of 0.6±0.4 years on stavudine, suggesting that the recent and cumulative stavudine exposure contributed to the toxicity. When controlling for other LAHL risk factors, switch to zidovudine conferred 80% lower hazards of LAHL for this subgroup (HR 0.21, 95% CI 0.07–0.64, p = .006). The remainder of women in this subgroup of obese women, initiated on stavudine and switched to zidovudine, included two who subsequently had anemia and two who died; the rest were followed until the end of the study, change in service provider, or a maximum of two years of follow-up without adverse events.
In our study of 2062 HIV-positive patients who initiated ART, stavudine use confers a fourteen-fold increased risk of developing hyperlactatemia or lactic acidosis when controlling for other risk factors (HR 14.31, 95% CI 5.79–35.30). Other risk factors for the primary outcome of LAHL were female sex, higher baseline BMI, higher baseline creatinine or albumin, and lower initial CD4 cell count. For patients who started a stavudine-containing regimen, switching to zidovudine was associated with 85% lower hazards of developing LAHL (HR 0.15, 95% CI 0.06–0.35). For the high-risk subgroup of women with BMI≥25 kg/m2 who initiated therapy on stavudine-containing ART, switch to zidovudine was also protective when controlling for other risk factors (HR 0.21, 95% CI 0.07–0.64).
Our study adds to the literature by demonstrating that female sex is a strong
independent risk factor for developing LAHL
Higher creatinine was associated with increased hazards of LAHL, about 25% per
1 mg/dL unit increase in creatinine. This risk factor has not been reported in prior
univariate analyses and has not been included in studies that control for other risk
factors, but is not unexpected given the kidney's role in lactate metabolism
The Lactic Acidosis International Study group showed an association of older age (age
>40 years) with the development of LAHL. This was not seen in our cohort nor in
other studies based in Southern Africa
For the subgroup of women with higher BMI, stavudine use, when controlling for other risk factors, remained associated with a significant increase in risk of LAHL. Switching these women to zidovudine conferred an 80% reduction in hazards of LAHL. These data suggest that higher-risk individuals should be switched off stavudine-based therapy in order to reduce adverse events.
There are several limitations to this study. The two treatment groups were quite
different as demonstrated in
As of April 2010, first-line ART in South Africa includes tenofovir, lamivudine, and
either efavirenz or nevirapine
We would like to acknowledge the patients, clinicians and monitoring and evaluation staff at Sinikithemba. We would also like to acknowledge data capturers and McCord volunteers Lisa Bevilacqu, Anthony Sawyer, Winn Seay, Mary Gallo, Dr. Hannah Willoughby, and Dr. Eileen Scully. We are also grateful to Dr. Heather Ribaudo of the Harvard University Center for AIDS Research Biostatistical Core and Dr. Roger Davis for statistical support.