As seen in Table 1, the 4 most common first-line regimens were stavudine (d4T) plus lamivudine (3TC) plus NVP (63%), zidovudine (AZT) plus 3TC plus NVP (19%), d4T plus 3TC plus EFV (9%), and AZT plus 3TC plus EFV (4%). Over a follow-up of 2330 person-years, 285 (20%) patients modified therapy and 126 (9%) discontinued their first-line regimen (Table 2). Of those who discontinued therapy, almost half subsequently restarted the same regimen.
Two hundred eighty-five patients (20%) modified their first-line regimen. The following were the main reasons for those modifying therapy: AE (64%), cost (19%), and treatment failure (14%). Older patients were more likely to modify their regimen (odds ratio [OR] = 2.0, 95% confidence interval [CI]: 1.3 to 3.1); however, gender, CD4 cell count, presence of an AIDS-defining illness, hemoglobin, and body mass index (BMI) at time of initiation of therapy were not significantly associated with modifying therapy.
Overall, 13% (n = 183) patients substituted therapy because of the occurrence of an AE. The most common AEs in this group of patients were itching and/or skin rash (66%; not including mild allergic rash) and hepatotoxicity (27%). The median CD4 counts at initiation of therapy for those who developed a rash or hepatotoxicity were 113 cells/μL and 65 cells/μL, respectively. Other AEs included nausea and vomiting (25%) and anemia (23%). Twenty-seven (15%) of the 183 patients who substituted therapy because of AEs did so because of d4T-related toxicities (persistent symptomatic peripheral neuropathy [13%] and lipoatrophy [2.2%]). The median time on therapy before substitution because of any AE was 40 days (range: 1-2319 days).
As seen in Table 3, study patients were stratified into 2 groups: those on NVP-containing regimens and those on “other” (non-NVP) regimens. Eighty-three percent (n = 1195) of patients were on NVP-containing regimens. Of those on NVP-containing regimens, 156 (13%) substituted therapy because of an AE. Rash and hepatotoxicity accounted for 41 (26%) and 33 (21%) AEs, respectively. Those on NVP were more likely to substitute therapy because of AEs (P < 0.001), and the other regimens group was more likely to change therapy because of cost (P < 0.001; see Table 3). Those on NVP substituted therapy sooner than those on other regimens when the reason was an AE (median number of days: 34 vs. 74; P = 0.29), whereas those on other therapies changed therapy sooner when the reason for modifying therapy was cost (median number of days: 128 vs. 228; P = 0.16). The median time to development of hepatotoxicity on NVP was 34 days (range: 2-575 days). Of the 33 patients with hepatotoxicity, 27 (82%) were on rifampicin-containing anti-TB medications at the time of development of the AE.
Of the 183 patients who initially substituted therapy because of an AE, 15 (1%) discontinued their second-line regimen and 60 (33%) modified their second-line regimen, moving to a third-line regimen in a median time of 97 days. Of the 60 patients previously cited, 22 (37%) substituted therapy because of an AE, 11 (18%) switched because of treatment failure, and 10 (17%) changed therapy because of the cost of the second-line regimen.
Of the overall 3% of patients who switched because of treatment failure, (Table 4), 18 switched after the occurrence of an opportunistic infection while on therapy, 29 switched because of immunologic failure, and 3 switched because of virologic failure. Median time to switching therapy because of treatment failure was 406 days (range: 93-1008 days). Of the 40 patients who switched because of treatment failure, 3 eventually discontinued therapy and 18 modified therapy again to move on to a salvage regimen.
Cost was the primary reason (n = 81) for discontinuing any ART, followed by an AE (21%) and treatment failure (1.6%). The median time on therapy before discontinuing was 124 days (range: 1-1050 days). Those with higher CD4 counts (>200 cells/μL) at the time of initiation of therapy more frequently discontinued therapy (OR = 2.5, 95% CI: 1.5 to 4.3). Age, gender, presence of an AIDS-defining illness, hemoglobin, and BMI at the time of initiation were not significantly associated with discontinuing therapy.
Cost was also the third most common reason for modifying therapy. 3TC plus d4T plus NVP, the most commonly used regimen, costs approximately $20 per month. 3TC plus AZT plus NVP, the next most commonly used regimen, costs $25 per month. Combinations with EFV are almost twice as expensive, at $50 to $58 dollars per month. PI-based regimens cost almost $140 per month.
At the YRG CARE, a tertiary HIV care and research center in a resource-constrained setting, more than half the patients who needed ART according to WHO guidelines10 had initiated therapy by 2004. This is in stark contrast to the mere 8.2% of patients who initiated therapy at this center between 1996 and 1999.11 This change is attributable to the introduction of generic ART at a lower cost in the year 2000. Since this time, the number of people initiating ART has drastically increased and HIV-related morbidity and mortality have significantly declined.1
It is interesting to note that although 95% of infections were most likely acquired heterosexually, 82% of those on therapy were male. Part of this gender disparity might be explained by the fact that we included only those patients who were ART naive before initiation of triple HAART, effectively excluding women who previously received monotherapy with AZT or single-dose NVP during pregnancy. It is likely that this disparity between the number of male and female patients on therapy has more to do with the social and economic standing of women within the family unit and in society at large, however.
In this cohort, antiretroviral regimens were modified for a number of reasons, but as has been the case in many studies from the developed world,6-8 occurrence of AEs was the most common reason, accounting for 13% of the entire cohort and 63% of patients modifying therapy. As expected, those who substituted drugs because of an AE substituted earlier than those who switched because of treatment failure or cost.
Most patients at the YRG CARE were on NVP-containing regimens and were more likely to substitute therapy because of AEs than patients on other therapies. Rash and hepatotoxicity were the most common AEs noted in the NVP cohort. Median time to development of hepatotoxicity was 34 days. WHO guidelines recommend laboratory monitoring every 6 months after initiating therapy.10 In light of our data, however, earlier laboratory monitoring for toxicity is advisable. In addition, 87% of patients were on rifampicin-containing anti-TB medications at the same time. The cost of alternative regimens that are less hepatotoxic limits their use in resource-constrained settings. Further research is needed on HIV-TB drug toxicities and interactions and on how best to avoid them.
The most common and least expensive ($20 per month) first-line regimen used in this context is d4T plus 3TC plus NVP. EFV-based therapies are almost twice as expensive, and PI-based regimens are almost 7 times more expensive. Despite the high incidence of d4T-related toxicities, including lipoatrophy and peripheral neuropathy, d4T continues to be widely used in resource-constrained settings because of its low cost. Efforts should be made to replace d4T with alternative affordable drugs. In addition, more than 80% of our cohort was on NVP-containing regimens, also known to have a significant risk of causing hepatotoxicity. Once again, availability at low cost necessitates the use of this drug. Although patients were more likely to substitute earlier from NVP because of toxicity, they changed therapy earlier because of cost if they were on other regimens. The fine balance between tolerability and affordability needs to be considered when making treatment decisions in resource-constrained environments.
Most patients in India pay out of pocket for their HIV treatment. Almost 9% of patients discontinued therapy after approximately 4 months, usually because of the cost of therapy. Even though the cost of ART has fallen drastically in the past few years, it still remains out of the reach of many Indians with HIV. Approximately half of the patients who stopped therapy restarted on the same therapy, presumably after their financial situation improved. Inconsistent therapy can be harmful and can put the patient at risk for developing resistance to the less expensive regimens and force the patient to eventually go off therapy or to move to second- or third-line agents, which are often more expensive and less likely to be affordable to a patient who already stopped taking a first-line regimen because of cost. This underlines the importance of financial counseling and long-term financial planning that might help patients to remain on therapy without interruptions. International donor programs or government ART roll-out programs, which provide free or low-cost ART, can play an important role in removing cost as a barrier to treatment success.
Consistent with studies from the developed world, treatment failure was not the major reason for switching therapy.6-8 A significant number of people did experience clinical or immunologic failure, however. Almost half of the patients who switched because of treatment failure did so after the occurrence of an opportunistic infection, and 70% switched after a decline in CD4 cell count; the median time to switching was approximately 13 months. This is in contrast to reports from the developed world, where most patients who switched because of treatment failure did so as the result of an unsuppressed viral load.6-8 Studies show that virologic failure, reflected by a rise in PVL, or the lack of adequate suppression of viral load occurs before immunologic or clinical failure.11 Monitoring viral load can facilitate early detection of treatment failure and avoid the unnecessary morbidity experienced by our patients. Few viral load levels were available for the patients in our study because of the high cost of monitoring them. Although routine viral load testing is part of the guidelines from the US National Institutes of Health12 and is used widely in the developed world, the WHO guidelines for the developing world do not recommend it because of concern about its high cost. Efforts should be made to develop cost-effective means of quantifying PVL suitable to resource-constrained settings.
In conclusion, a significant number of people substituted therapy because of toxicities. The most frequently used NVP-containing regimens, although less expensive, were more likely to be associated with toxicities. Because of lack of resources for early detection of treatment failure through viral load monitoring, most of those who experienced treatment failure had clinical or immunologic failure as the indication for switching therapy. Less expensive and more tolerable first-line regimens as well as cost-effective treatment monitoring tools are needed to achieve better treatment outcomes and improve access in resource-constrained settings. More studies are needed from the developing world to establish criteria for substituting and switching therapy, evaluate the best combinations for second-line therapy, and direct treatment guidelines for resource-constrained settings.
The authors are grateful to A. Priya Cristy Bai and the research nurses as well as all the clinical staff at the YRG CARE, Voluntary Health Services, Chennai, India for their facilitation of the study. The authors thank S. Anand, K. Jayakumar, and T. Guru for database management.
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Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
HIV; AIDS; antiretroviral therapy; generic highly active antiretroviral therapy; toxicities; switch; India; resource-limited setting