Patients and Methods

Study site, clinic procedures, data collection. This study was conducted with the Themba Lethu Clinical Cohort, a cohort of adults initiating HAART at one of the largest public clinics providing HAART in South Africa. After initiating HAART in accordance with the South African National Comprehensive Care, Management and Treatment Guidelines for HIV and AIDS [16], patients are scheduled for clinical visits at 4 months and every 6 months thereafter; at these visits, demographic, medical, and laboratory data are collected. All data were entered into a TherapyEdge-HIV (TherapyEdge) database and analyzed with SAS, version 9.1 (SAS Institute).

Patients who required TB treatment received a standardized course of directly observed therapy at primary health care clinics (outside of Themba Lethu Clinic) in accordance with national treatment guidelines. Date of TB treatment initiation was obtained using TB patient clinic card and patient self-report to ensure accuracy. The standard first line of TB treatment in South Africa is 2 months of therapy with isoniazid, rifampicin, pyramizade, and ethambutol, followed by 4 months of therapy with isoniazid and rifampicin [16]. In South Africa, vitamin B6 (pyridoxine) is commonly prescribed at initiation of TB treatment. In the Themba Lethu Clinic, amitriptyline is commonly prescribed for individuals who experience peripheral neuropathy [19].

Study eligibility and definitions. Patients were eligible for analysis if they initiated a stavudine-containing HAART regimen at Themba Lethu Clinic from 1 April 2004 through 31 March 2007. The exposure of interest was TB treatment, defined as patient treatment with isoniazid-containing therapy for pulmonary or extrapulmonary TB. We hypothesized that the effect of TB treatment on the risk of stavudine substitution might be affected by the relative timing of HAART initiation and TB treatment; to this end, we analyzed 3 exposure categories. Ongoing TB treatment was defined as TB treatment started at least 15 days before initiation of HAART, which is the minimum period advised by the National Guidelines and the World Health Organization (WHO) to wait between initiation of TB treatment and initiation of HAART [16, 20]. Concurrent TB treatment was defined as initiation of both TB treatment and HAART within 14 days of each other. Incident TB treatment was defined as initiation of TB treatment at least 15 days after initiation of HAART, a cutoff point that was chosen to mirror the ongoing TB treatment category. A schematic diagram for these exposure categories is shown in figure 1. For all exposures, the comparison group comprised individuals not receiving TB treatment. The outcome of all-cause stavudine substitution was defined as the event of substitution of a single drug (most often zidovudine) for stavudine while the rest of the regimen remained unchanged. Patients were followed up until they had experienced the event of interest or until censoring at the time of a second episode of TB while receiving HAART, death, loss to follow-up, multidrug substitution, or end of the follow-up period (31 March 2007).

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Figure 1

Schematic diagram of tuberculosis treatment exposure categories in relation to time of highly active antiretroviral therapy (HAART) initiation (ongoing, concurrent, or incident).

Statistical analyses. We performed an intent-to-treat analysis, controlling for confounding and censoring using inverse probability weighted marginal structural Cox proportional hazards models [21–23]. These methods are similar to Cox proportional hazards models and account for confounding by both baseline and time-varying factors where appropriate; in addition, these models can adjust analytically for losses to follow-up [24] and competing risks [25]. We controlled for confounding by sex, ethnicity, employment status, age, history of antiretroviral therapy, previous history of TB treatment, pregnancy, peripheral neuropathy at HAART initiation, hemoglobin level (adjusted for sex, pregnancy, and altitude), body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), CD4 ⁺ cell count, WHO stage, calendar date, whether treatment was initiated after October 2006 (when all consultation fees were eliminated), and stavudine dosage (milligrams per kilogram).

In these analyses, patients were considered to have become exposed at the earliest time that they were receiving both HAART and TB treatment. However, we expected the effect of TB treatment to change with total time receiving both TB treatment and HAART. Time-interaction terms were included in all analyses to allow models to estimate these different effects by months of cotreatment: 0–2 months, 3–6 months, and ⩾7 months. Last, we performed several sensitivity analyses (described below). Additional details of the statistical analysis are given in the Appendix (online only).

Ethics approval. This study was approved by the human subjects review boards of both the University of the Witwatersrand (Johannesburg, South Africa) and the University of North Carolina at Chapel Hill.

Results

We analyzed data for 7066 individuals who initiated stavudine-containing HAART, among whom there were a total of 1845 cases of active TB. Of these cases, 1272 involved ongoing TB treatment (treatment had been received for >60 days in 716 cases and for 15–60 days in 556 cases), 224 involved concurrent initiation of treatment, and 349 involved incident TB treatment (TB treatment was initiated within 15–60 days of HAART initiation in 132 case and >60 days of HAART initiation in 217 cases). Patients with either ongoing or concurrent TB treatment were less likely to have a history of TB at the time of HAART initiation and were more likely to be male and to have advanced disease (i.e., lower CD4 ⁺ cell count, low BMI, low hemoglobin level, and a greater prevalence of WHO stage IV disease), compared with those not receiving TB treatment, and they were more likely to receive a reduced (30-mg) dose of stavudine (table 1). Patients who later developed TB likewise had lower baseline BMI, CD4 ⁺ cell count, and hemoglobin level than did patients who were not receiving TB treatment at baseline, and they were similarly more likely to receive a reduced dose of stavudine.

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Figure 2

Kaplan-Meier analysis of time to stavudine substitution by tuberculosis (TB) treatment status at time of highly active antiretroviral therapy (HAART) initiation, among 7066 individuals initiating HAART in Johannesburg, South Africa.

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Table 1

Baseline characteristics of 7066 individuals at time of highly active antiretroviral therapy (HAART) initiation in Johannesburg, South Africa, by timing of tuberculosis (TB) treatment status as it relates to HAART initiation.

Of the 7066 patients enrolled in the study, 260 (3.7%) died, 1252 (17.7%) became lost to follow-up, and 1219 (17.3%) experienced stavudine substitutions. Of these, 842 were single-stavudine substitutions, 203 were multidrug substitutions, and 172 were switches to second-line HAART (zidovudine, didanosine, and lopinavir-ritanovir). The crude rate of single-stavudine substitution in the entire cohort was 12.4 (95% confidence interval [CI], 11.6–13.3) per 100 person-years, with a median time to single-stavudine substitution of 347 days (interquartile range [IQR], 175–535 days). As expected, the absolute rate of stavudine substitution increased with time after HAART initiation, from months 0–6 (7.9 substitutions per 100 person-years; 95% CI, 6.9–9.1), to months 6–12 (12.3 substitutions per 100 person-years; 95% CI, 10.8–14.0), and to the rest of follow-up (18.1 substitutions per 100 person-years; 95% CI, 16.4–20.0). This increasing rate is evident in figure 2, which shows Kaplan-Meier curves for single-stavudine substitutions stratified by baseline TB treatment exposure category. These curves show an increased risk of stavudine substitution in the first months of concomitant TB treatment and HAART, compared with the risk for those not receiving TB treatment, and shows no increased risk attributable to TB treatment after 6 months; at the same time, these curves show that the absolute rate of stavudine substitution increases at 6 months and again at 1 year.

Hazard ratios adjusted for confounding, loss to follow-up, death, and the competing risk of multidrug substitution are shown in table 2. Crude results were similar to adjusted results (data not shown). Among people who were receiving ongoing TB treatment at the time of HAART initiation, adjusted hazard ratio (aHR) for stavudine substitution was 3.18 (95% CI, 1.82–5.56) in the first 2 months of HAART, 2.51 (95% CI, 1.77–3.54) for months 3–6, and 1.19 (95% CI, 0.94–1.52) thereafter. Among people who received concurrent initiation of treatment for TB and HAART, the aHR was 6.60 (95% CI, 3.03–14.37) in the first 2 months of HAART, 1.88 (95% CI, 0.87–4.09) for months 3–6, and 1.07 (95% CI, 0.65–1.76) thereafter. Among people with incident TB treatment after HAART initiation, the aHR was not different from that for the referent group and was imprecise in all 3 time periods (table 2). Early incident TB treatment tended to be associated with increased risk of stavudine substitution in the first 2 months of cotreatment with an aHR of 2.74 (95% CI, 0.84–8.94).

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Table 2

Adjusted hazard ratios and 95% confidence intervals for the effect of tuberculosis (TB) treatment on stavudine substitution, by timing of TB treatment initiation relative to highly active antiretroviral therapy (HAART) initiation and duration of cotreatment, among 7066 individuals initiating HAART in Johannesburg, South Africa.

Almost one-half of the single-stavudine substitutions (362 [43%] of 842) were attributed to clinically diagnosed peripheral neuropathy, 205 (24%) were attributable to lipodystrophy, 168 (20%) were attributable to lactic acidosis or symptomatic hyperlactatemia, and 21 (2%) were attributable to a combination of these toxicities; the remainder (86; 10%) had no reason recorded. Patients who switched because of peripheral neuropathy were more likely to have TB at HAART initiation or during follow-up (risk ratio [RR], 1.53; 95% CI, 1.33–1.75), whereas those who switched because of lactic acidosis or lipodystrophy were less likely to have TB (RR, 0.58; 95% CI, 0.48–0.71).

Sensitivity analysis. Sensitivity analyses indicated that the main results were not sensitive to absolute stavudine dose (30 vs. 40 mg), inclusion of multidrug substitutions, or total TB treatment lasting 9 months (rather than 6 months). We found that restricting analysis to patients without a history of TB resulted in slightly elevated hazard ratios for both ongoing and concurrent analyses in months 0–2 (for ongoing analysis, aHR of 3.56 vs. baseline scenario aHR of 3.18; for concurrent analysis, aHR of 7.57 vs. baseline scenario aHR of 6.60). This suggested that lingering peripheral neuropathy from previous drug exposures might have biased the results toward the null.

Discussion

Concomitant administration of TB treatment and HAART is common in sub-Saharan Africa, especially at HAART initiation. Our results show that concurrent initiation of TB treatment and stavudine-based HAART within a 2-week window puts patients at a nearly 7-fold increased risk of stavudine substitution in the first 2 months of HAART (aHR, 6.60; 95% CI, 3.03–14.37) and at some increased risk until 6 months after HAART initiation. Likewise, initiation of stavudine for patients whose TB treatment was ongoing for >2 weeks at the time of HAART initiation was associated with a 2- to 3-fold increased risk of stavudine substitution during the first 6 months of HAART. The presence of an effect of both ongoing and concurrent TB treatment within 6 months after HAART initiation are evident in crude results shown in figure 2, where survival curves diverge sharply in the first 6 months but are similar (essentially parallel) thereafter. In general, there was little-to-no effect of incident TB treatment on the risk of stavudine substitution, although there was a suggestion that early incident TB might increase the risk of stavudine substitution. Risks remained elevated even among patients who received a twice-daily 30-mg dose of stavudine, in accordance with current WHO recommendations, and these risks were not confounded by stavudine dosage (milligrams per kilogram). These results, which were based on a large sample size and robust analytic methods, confirm and extend the results of 2 small studies from England, in which higher-than-expected rates of adverse events were observed among patients receiving concomitant stavudine and TB treatment [26, 27].

Almost one-half (43%) of single-stavudine substitutions could be attributed to peripheral neuropathy; individuals who received TB treatment were more likely than others to switch because of peripheral neuropathy (risk ratio, 1.53). This is consistent with the hypothesis that peripheral neuropathy is a key symptomatic pathway for the interaction of TB drugs and HAART. Peripheral neuropathy is caused by both isoniazid [10, 18] and stavudine [3, 14, 17, 18, 26, 27], through different mechanisms; use of both drugs may lead to an additive or cumulative effect and increase the severity of symptoms.

Indeed, these results may understate the true impact of stavudine and TB treatment, for 3 reasons: first, because the great majority of patients with TB in South Africa are prescribed vitamin B6 (pyridoxine) at the time of initiation of TB treatment for the prevention of peripheral neuropathy, and in addition, amitriptyline is frequently prescribed to manage incident peripheral neuropathy. It is possible that the effect of TB on the risk of stavudine substitution would be even higher in settings where these drugs were not routinely used; conversely, rates of peripheral neuropathy may be further reduced with additional micronutrient supplementation [28].

Second, restricting the reference group to individuals without a history of TB yielded higher effect estimates for analysis of concurrent and ongoing TB treatment. This suggests that the main analyses could have underestimated the true impact of TB treatment on the risk of stavudine substitution, perhaps because of residual peripheral neuropathy among those with a recent history of TB treatment.

Third, although focusing on stavudine substitution as the outcome ensures that we capture the most-severe toxicities, we did not examine the impact of TB treatment on the risk of mild stavudine toxicity. It is likely that treatment for TB resulted in additional low-level peripheral neuropathy, which may remain undiagnosed or unreported, or resolve without stavudine substitution. Thus, the impact of TB treatment on the risk of stavudine toxicities may be higher than the impact of TB treatment on the risk of stavudine substitution.

It was surprising that incident TB treatment—and in particular, late incident TB treatment—was not associated with an increase in the risk of stavudine substitution; this may be the result of a depletion of susceptible patients. An alternate hypothesis is that the effect of TB treatment on the risk of stavudine-related toxicity is mediated by HIV load. Control of HIV replication would then reduce the effect of TB treatment on the risk of stavudine substitution.

TB treatment did not increase risk of stavudine substitution after 6 months (which is the duration of a typical course of TB treatment). However, the bulk of stavudine substitution occurs >6 months after treatment initiation; it is important to note that, although the relative rate of stavudine substitution attributable to TB treatment was not statistically significant after 6 months in any exposure group, the absolute rate of stavudine substitution increased substantially after both 6 and 12 months of HAART. A related point is that, because the absolute risk of stavudine substitution is relatively low during the 6 months after initiation of stavudine treatment, even a large hazard ratio may translate into a relatively small absolute risk difference. Only 219 stavudine substitutions took place during the first 6 months after initiation of HAART among patients who were at risk for that period. The absolute risk for those with any TB treatment at baseline (ongoing or concurrent) was 5.7%; for those without TB treatment, the absolute risk was 2.4% (risk difference, 3.3%; 95% CI, 2.0%–4.5%), corresponding to 1 stavudine substitution for every 18 patients with TB treatment and 1 stavudine substitution for every 42 patients without any TB treatment. Because of the large number of individuals in this population who initiate HAART while receiving TB treatment (>20%), we believe that these results remain of considerable public health relevance.

There were several limitations to this study. First, this observational study was conducted in a busy clinic setting using routinely collected data; therefore, the results are necessarily less definitive than they would be in a randomized trial. In particular, although we strove to control adequately for confounding, uncontrolled confounding may still be present, including exposure to alcohol and other drugs associated with peripheral neuropathy. Similarly, although we corrected for bias caused by competing risks, including death, loss to follow-up, and multidrug substitution, complete control of such bias depends on the difficult-to-verify assumption that competing risks can be completely explained by observed variables [24, 25]. Lastly, if patients receiving stavudine and isoniazid were evaluated more thoroughly for peripheral neuropathy than were comparable patients, this might lead to detection or diagnostic bias that might result in an overestimation of the effect. Future studies of this topic should use blinded evaluation of peripheral neuropathy to eliminate this potential bias.

In conclusion, our results show that concurrent initiation of TB treatment and HAART, as well as initiation of HAART while receiving ongoing TB treatment, is an important risk factor for stavudine substitution in this patient population, irrespective of stavudine dosage. These results suggest that screening for peripheral neuropathy is important for patients who receive stavudine and TB treatment, especially for those initiating both treatments within a short period. Moreover, where alternative antiretroviral drugs are available, we may wish to reconsider the use of stavudine in first-line HAART for patients with ongoing or concurrent initiation of TB treatment.