Fox MP, Ive P, Long L. High rates of survival, immune reconstitution and virologic suppression on second-line antiretroviral therapy in South Africa. J Acquir Immune Defic Syndr. 2009 Oct 15.
With the increased use of antiretroviral therapy (ART) in resource-constrained areas, the number of persons failing first-line therapy is likely to increase. In addition, the continued use of single-dose nevirapine to prevent mother-to-child transmission increases the probability of resistance to nevirapine in women who later receive it as part of ongoing treatment.(1, 2)
To determine the effectiveness of second-line ART in resource-limited areas
A large, urban outpatient HIV clinic in South Africa
Prospective cohort study
All adult (≥18 years of age) patients who initiated second-line ART (AZT, didanosine, and lopinavir/ritonavir) who had previously received standard first-line therapy (stavudine, lamivudine, and efavirenz) between April 2004 and June 2008
Survival, virologic suppression, CD4 counts among patients who switched to second-line therapy compared to matched controls who remained on first-line treatment
Demographic and clinical data are maintained in an electronic patient management system. Demographic data were obtained when the patients initiated first-line therapy. Patients are routinely seen for medical care every one to six months but return to the clinic every one to two months for new medication. Clinic appointments are tracked in the patient management system. Treatment monitoring is done with CD4 counts and viral load measurements four months after treatment initiation and every six months thereafter, unless clinically indicated earlier.
Each patient on second-line treatment was time-matched to four controls who did not switch but had been on therapy at least as long as the index patient. All but one index patient matched with four controls. Survival time began after the period in which the index patient had been on first-line therapy.
There were 328 index patients and 9694 controls. Among the entire cohort of patients who ever initiated first-line therapy, 21.4% were lost to follow-up, 9.6% died, and 5.4% transferred care. The switch to second-line therapy occurred at a median of 1.3 years. Compared with patients who had not switched to second-line treatment and with time-matched comparisons, patients who switched had more immunosuppression at initiation of first-line therapy. This result occurred because they were more likely to have had a CD4 count ≤50 cells/µL than both comparison group (43% vs. 35% and 32%, respectively) and more likely to have had a history of tuberculosis (19% vs. 9% and 11%, respectively). For the 287 patients who had two detectable viral loads >1000 before switch, the median time from the first detectable viral load to switch was 84 days (interquartile range [IQR] 32-183). The median viral load at the second detectable viral load was 13,000. For the 41 patients who did not have such records, more than half (n = 22) had confirmed virologic failure listed as the reason for treatment switch.
Seventy-eight percent (95% confidence interval [CI]: 73%- 82%) of patients who switched to second-line treatment (243/313) were alive and in care at the end of one year. Seventeen patients died (24%) in a median of four months (IQR 0.9-7.7). The remaining 53 were lost to follow-up (76%) in a median of 5.6 months (IQR 3.7-9.0). Fifteen patients who transferred care were excluded.
Viral load measurements were available for 262 patients, of whom 203 (77%; 95% CI: 72%-82%) were virally suppressed by one year on second-line treatment. Median time to viral suppression was 118 days (IQR 96-150). Of the 59 patients who did not achieve viral suppression, median viral load was 7000 (range 450-130,000). Of these patients, 30 (51%) were still alive and in care at the end of one year of follow-up. Of the remaining 29 patients, 8 (14%) died, 19 (32%) were lost to follow-up, and two transferred out of care (3%). Among those with viral suppression by one year, 18 (9%; 95% CI: 6%-13%) had viral rebound within one year of initiating second-line with a median viral load of 1700 (range 420-62,000).
Mean CD4 gain by 12 months was 133 cells/µL (95% CI: 106-160). Patients on second-line therapy had a small decreased likelihood of being alive and in care by one year (hazard ratio [HR] 0.84; 95% CI: 0.73-0.97) as time-matched comparisons on first-line ART.
A smaller proportion of patients on second-line therapy were alive and in care after one year on treatment compared with time-matched comparison patients still on first-line ART (77% vs. 91%). After adjusting for age, sex, race, first-line regimen, and year of initiating any ART, patients on second-line therapy were somewhat less likely to be alive and in care by one year (HR 0.84; 95% CI: 0.73-0.97) than those still on first-line for equal duration.
The independent predictors of virologic suppression among patients on second-line therapy were being switched to second-line for reasons other than noncompliance (HR 1.83; 95% CI: 1.14-2.93), being switched before having two consecutive detectable viral loads (HR 1.68; 95% CI: 1.08-2.61), not having a history of tuberculosis (HR 1.39; 95% CI: 0.95-2.04), having a body mass index ≥17.5 at initiation of any ART (HR 1.67; 95% CI: 0.97-2.88) and having a CD4 count >200 at initiation of any ART vs. <100 (HR 1.96; 95% CI: 1.21-3.17). The CD4 count at initiation of second-line therapy or CD4 nadir was not predictive of viral suppression.
Patients who were initiated on second-line therapy in a large urban HIV clinic in Johannesburg, South Africa, had high rates of immunologic and virologic success and low rates of mortality over the first year on second-line treatment.
Based upon the Newcastle-Ottawa assessment scale, this was a very good study. The only weakness was that information on the representativeness of the sample was not provided; however, based upon the setting from which participants were selected, the sample is likely to be representative of HIV-infected persons in care in the region. In all other respects the sample selection, outcome assessment, and follow-up were excellent.
The findings from this paper are encouraging and indicate good clinical outcomes among persons in a resource-constrained area who switched to second-line therapy. Similar findings were reported in another cohort.(3) Based upon years of experience in developing countries, with expanded use of first-line ART, treatment failure will follow to a certain extent and having an understanding of the predictors of success following a change from first- to second-line therapy can guide clinicians, particularly in areas where viral load testing and second-line ART are not readily available.
- Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007; 356:135-47.
- Arrive E, Newell ML, Ekouevi DK, et al. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol. 2007;36:1009-21.
- Pujades-Rodriguez M, O'Brien D, Humblet P, et al. Second-line antiretroviral therapy in resource-limited settings: the experience of Medecins Sans Frontieres. AIDS. 2008;22:1305-12.