Second-line antiretroviral therapy in resource-limited settings: the experience of Me´decins Sans Frontie`res Mar Pujades-Rodrı´, Daniel O’BrienPierre Humblet Objectives: To describe the use of second-line protease-inhibitor regimens in Me´de-cins Sans Frontie`res HIV programmes, and determine switch rates, clinical outcomes,and factors associated with survival.
Design/Methods: We used patient data from 62 Me´decins Sans Frontie`res programmesand included all antiretroviral therapy-naive adults (> 15 years) at the start of anti-retroviral therapy and switched to a protease inhibitor-containing regimen with at leastone nucleoside reverse transcriptase inhibitor change after more than 6 months ofnonnucleoside reverse transcriptase inhibitor first-line use. Cumulative switch rates andsurvival curves were estimated using Kaplan–Meier methods, and mortality predictorswere investigated using Poisson regression.
Results: Of 48 338 adults followed on antiretroviral therapy, 370 switched to a second-line regimen after a median of 20 months (switch rate 4.8/1000 person-years). MedianCD4 cell count at switch was 99 cells/ml (interquartile ratio 39–200; n ¼ 244). Alopinavir/ritonavir-based regimen was given to 51% of patients and nelfinavir-basedregimen to 43%; 29% changed one nucleoside reverse transcriptase inhibitor and 71%changed two nucleoside reverse transcriptase inhibitors. Median follow-up on second-line antiretroviral therapy was 8 months, and probability of remaining in care at 12months was 0.86. Median CD4 gains were 90 at 6 months and 135 at 12 months. Deathrates were higher in patients in World Health Organization stage 4 at antiretroviraltherapy initiation and in those with CD4 nadir count less than 50 cells/ml.
Conclusion: The rate of switch to second-line treatment in antiretroviral therapy-naiveadults on non-nucleoside reverse transcriptase inhibitor-based first-line antiretroviraltherapy was relatively low, with good early outcomes observed in protease inhibitor-based second-line regimens. Severe immunosuppression was associated with increasedmortality on second-line treatment.
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Keywords: Africa, antiretroviral therapy, low-income population, resource- limited setting, reverse transcriptase inhibitors, second line, viral load inhibitor (NNRTI) antiretroviral drugs. Satisfactory short-term outcomes in such settings have been described by Since 2001, Me´decins Sans Frontie`res (MSF) has provided MSF and others , and this contributed to the rapid antiretroviral therapy (ART) to more than 100 000 people scaling up of ART. As access to and time on ART increases, in resource-limited settings (RLS), using World Health the need for second-line regimens in RLS becomes a Organization (WHO)-recommended first-line regimens priority due to the development of drug resistance involving two nucleoside reverse transcriptase inhibitor Clinical programme data are urgently needed to help design (NRTI) and one non-nucleoside reverse transcriptase longer-term treatment strategies, and to allow programme From the aEpicentre, the bMe´decins Sans Frontie`res (MSF) AIDS Working Group, Paris, France, and the cCampaign for Access toEssential Medicines, MSF, Geneva, Switzerland.
Correspondence to Mar Pujades, Epicentre, Paris, France.
E-mail: Received: 29 October 2007; revised: 16 January 2008; accepted: 18 January 2008.
ISSN 0269-9370 Q 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
managers, governments, donors, and pharmaceutical Although virological monitoring was not routinely manufacturers to more accurately forecast antiretroviral performed, viral load was occasionally determined when drug first-line and second-line requirements clinicians suspected treatment failure and adequatelaboratory facilities were available.
Detection of first-line ART failure in most RLS relies onimmunological or clinical criteria, as routine viral load monitoring is frequently not available due to financial and We analysed information from all ART-naive adults (> 15 technical constraints. Thus, diagnosis of failure is often years) at MSF programme inclusion and who received an delayed and might favour not only clinical disease NNRTI first-line regimen for more than 6 months. Missing progression but also development of antiretroviral age data was the only reason for exclusion from this study. To resistance due to concurrent antiretroviral drug exposure exclude antiretroviral drug substitutions for toxicity, we and high viral replication. The appearance of resistance defined second-line therapy as a concomitant initiation of a mutations [e.g. thymidine analogue mutations (TAMs)] protease inhibitor-containing regimen and a change in at may thus jeopardize the effectiveness of second-line ART least one NRTI drug in patients who had received NNRTI regimens in settings where few treatment options are first-line therapy for more than 6 months. Women who had available Additional constraints regarding second- received prevention of mother-to-child transmission line ART in RLS include availability of less robust (PMTCT) prophylaxis were considered naive. Reasons second-line ART regimens (e.g., nonboosted protease for switch to second line were not prospectively collected.
inhibitors); difficulty in ensuring long-term adherence Treatment failure was defined as CD4 at switch less than due to increased pill burden or meal restrictions; and high CD4 cell count at ART initiation; CD4 cell count at switch price of drugs (up to ten times more expensive than first- less than 100 cells; new WHO stage 3 or 4 event within line regimens) Therefore, concerns about the 3 months before switch; and/or viral load more than effectiveness of second-line ART in RLS have been We report here the rate of switch from first-line to We estimated the probabilities of remaining on first-line second-line ART in MSF programmes; survival and ART, rate of switch to second-line ART, and probabilities clinico-immunological outcomes of patients on second- of remaining alive and in care after first-line and second- line ART; and factors contributing to death when on line therapy initiation using Kaplan–Meier and censor- ing-naive methods. For patients on ART for more than19.8 months (the median time of follow-up on ARTbefore the switch to second line), we compared theprobabilities of remaining alive and in care in patients started or not on second-line therapy with the log-ranktest. We then described patient characteristics at the start of ART and at switch, and BMI and CD4 gains at 6, 12, We used routinely collected individual patient data and 24 months after switch, using medians, interquartile (FUCHIA software, Epicentre, Paris) from 62 MSF- ranges (IQR), and percentages, as appropriate. Finally, we supported HIV programmes in 26 countries between investigated factors associated with death or lost to October 2001 and December 2006. Data collected follow-up (LFU; a missed appointment for > 2 months) included sex; age; treatment history; ART prescription using Poisson regression. To control for the heterogeneity date and regimen; dates of visit, appointment, or death; of the data, as information from several projects was WHO clinical stage; and CD4 cell count and viral load, included (and access to CD4 testing and/or to diagnostic facilities for opportunistic infections vary in differentcontexts), all the models were adjusted for geography All programmes provided free care, including antire- (sub-Saharan Africa, Asia, and Latin America) and for troviral drugs and laboratory investigations, with clinical factors significantly associated with the outcomes (P value consultation performed by doctors, clinical officers, or from likelihood ratio tests < 0.05).
nurses. Eligibility criteria for ART were based on the2003 WHO recommendations and generic anti-retroviral drugs used, mainly in the form of NNRTI-containing fixed-dose combinations. Adherence counsel- ing was provided to all patients both prior to and duringART. Programmes routinely provided prophylaxis and Description of the global Me´decins Sans treatment of opportunistic infections and often nutri- tional support for malnourished individuals. CD4 cell After excluding 856 (1.7%) patients with unknown age, we counts were measured using either automated or manual analysed data from 48 338 naive adults on ART for more methods (Partec, Dynabeads, Beckton Dickinson).
than 6 months, 78% treated in MSF-supported projects in Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Second-line antiretroviral therapy Pujades-Rodrı´guez et al.
Africa, 18% in Asia, 4% in Latin America, and 0.2% in corresponding to a switch rate from first to second line of Eastern Europe . At the start of ART, patient 4.8/1000 person-years (95% CI 4.3–5.3) median age was 35 years (IQR 30–42), and 62% were Switch rates ranged from 4.2/1000 person-years in women. The median CD4 cell count was 110 cells/ml sub-Saharan projects to 6.5/1000 in Asia, 7.4/1000 in (IQR 46–178; n ¼ 34 799), and 84% were classified as Latin America, and 14.5/1000 in Eastern Europe. At WHO clinical stage 3 or 4. The first-line ART regimen the start of first-line ART, 334 (90%) patients were most frequently prescribed was stavudine/lamivudine/ in cumulative WHO clinical stage 3 or 4, and had a nelfinavir (d4T/3TC/NVP) (86%), and median duration of median BMI of 20 kg/m2 (IQR 18–22; n ¼ 321) and ART was 18 months (IQR 11–25), with 13 871 (29%) median CD4 cell count of 52 cells/ml (IQR 18–131; patients on treatment for more than 2 years. For patients on n ¼ 304). Median CD4 nadir was 39 cells/ml (IQR 13– regular follow-up, the probability of remaining on first-line ART after 36 months was 0.98 (95% CI 0.97–0.98). Theprobability of remaining alive and in care at 24 months At the time of switch, median CD4 cell count was 99 cells/ml (IQR 39–200; n ¼ 244), 32% having less than50 cells/ml, 50% had less than 100 cells/ml, and 75% had less than 200 cells/ml. Median viral load was 43 188 copies/ml (IQR 16 406–166 197; n ¼ 75), and A total of 370 (0.8%) patients began a second-line median BMI was 21 kg/m2 (IQR 19–24; n ¼ 320) with regimen after a median of 20 months (IQR 14–27), 45 (14%) patients having less than 17 kg/m2.
Table 1. Demographic and clinico-immunological characteristics of patients treatment-naı¨ve at the start of antiretroviral treatment (ART),Me´decins Sans Frontie`res (MSF) HIV cohort 2001–2006, 26 countries.
Characteristics at switchMedian CD4 cell count [IQR] (cells/ml) IQR are shown in square brackets and percentages in brackets. ABC, abacavir; BMI, body mass index; ddI, didanosine; EFV, efavirenz; d4T,stavudine; IQR, interquartile range; LPV, lopinavir; NFV, nelfinavir; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, proteaseinhibitor; TDF, tenofovir; 3TC, lamivudine; VL, viral load; ZDV, zidovudine.
aMedian months on ART (first line or second line).
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Table 2. Number of patients, cumulative person-years of follow-upand cumulative incidence of switches to second-line therapy, Me´decins Sans Frontie`res, HIV cohort 2001–2006, 26 countries.
Second-line treatment outcomesMedian follow-up on second-line ART was 8 months Fig. 1. Cumulative switch rates from first-line to second-line (IQR 2–18), with 138 (37%) patients on treatment for antiretroviral treatment (ART) and 95% confidence intervals more than 12 months. Twenty-eight (8%) patients died among naı¨ve patients at the start of ART, Me´decins Sans after a median of 5 months (IQR 3–8), and 18 (5%) were Frontie`res HIV cohort 2001–2006, 26 countries.
LFU after a median of 9 months (IQR 3–14). Recordedcauses of death were Kaposi sarcoma (n ¼ 7), tuberculosis During the 3 months before the switch, a new WHO (n ¼ 4), wasting syndrome (n ¼ 3), and one suspicion of clinical stage 3 or 4 condition had been recorded for 111 cerebral mass. The probabilities of remaining alive and in (30%) patients and a CD4 value of less than or equal to care at 12 and 24 months were 0.86 (95% CI: 0.81–0.90) CD4 cell count at the start of ART for 69 (34%). Among patients who were switched to second line, 230 (62%) had at least one of the criteria of treatment failure according to number of NRTI drugs changed (P ¼ 0.99) and were the 2006 WHO criteria. A total of 139 patients had no slightly, but not significantly, higher for patients on CD4 data collected and thus could not be evaluated with LPV/r-second-line therapy (unadjusted P ¼ 0.06, com- regard to immunological treatment failure criteria.
pared with NFV-based therapy). The probability ofremaining alive and in-care for patients with a follow- The protease inhibitor component of the second-line up of at least 19.8 months was similar in patients switched regimen was lopinavir/ritonavir (LPV/r) for 188 (51%) and not switched to second-line therapy at 20 months of patients and nelfinavir (NFV) for 160 (43%); 56% ART, but it was lower for patients on second line after that received a boosted protease inhibitor. The most (log-rank test P value 0.03; and . However, frequently administered NRTI combinations were latter estimates were based on data from few patients.
zidovudine-didanosine (ZDV-ddI; 34%) and abacavir(ABC)-ddI (22%). Only one NRTI drug had been Median CD4 cell count was 184 cells/ml (IQR 128–306; changed instead of two for 115 (31%) patients, and only n ¼ 106) and 247 cells/ml (IQR 132–302; n ¼ 78) at 6 12% received ZDV-lamivudine (ZDV-3TC) in combi- and 12 months, respectively. Median CD4 increase was 90 (37–141; n ¼ 73) and 135 (50–198; n ¼ 55) at 6 and Follow-up month after second-line ART switch Fig. 2. Probabilities of remaining in care, Me´decins Sans Frontie`res, HIV cohort 2001–2006, 26 countries. (a) Kaplan–Meierestimates of remaining in care after switch from first-line to second-line treatment in antiretroviral treatment (ART)-naive patients.
(b) Kaplan–Meier estimates of remaining in care after the start of ART in ART-naive patients for patients switched or not switched tosecond-line ART with a follow-up on ART of at least 19.8 months.
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Second-line antiretroviral therapy Pujades-Rodrı´guez et al.
Table 3. Number of patients and incidence of deaths or lost to follow-up, Me´decins Sans Frontie`res, HIV cohort 2001–2006, 12 months, respectively One year after switch, six (10.9%) patients had a CD4 cell count of less than50 cells/ml, 14 (25.5%) had less than 100 cells/ml, and 30 (54.5%) had less than 200 cells/ml. Furthermore, medianweight gains at 6 and 12 months after switch were 0.5 kg (IQR À2 to 3; n ¼ 205) and 1 kg (IQR À2 to 4; n ¼ 139), respectively. Only eight (6%; n ¼ 127) patients had a BMI of less than 17 kg/m2 1 year after the switch. After 6months of treatment, 46 (12.4%) patients developed aWHO condition stage 3 or 4 (14 at stage 4 condition), and the CD4 cell count was equal or below the value Fig. 3. Immunological response on second-line antiretro- Antiretroviral drug-related toxicity leading to cessation or viral treatment (ART), Me´decins Sans Frontie`res HIV cohort change of the antiretroviral drug regimen was recorded 2001–2006, 26 countries. Bars denote number of patients for only three (1%) patients: two on ZDV-ddI-NFV (primary Y axis). Line graph denotes CD4 cell count (neuropathy WHO grades 1 to 2 and lactic acidosis) and one on ZDV-ddI-IDV/r (hepatoxicity grade 4).
Factors associated with death and lost to Nine out of ten patients were still alive after 12 months of treatment, and few patients were diagnosed with new In multivariable analyses, death and LFU rates were severe AIDS-related illnesses. However, over half of the higher in patients classified as WHO stage 4 at first-line patients were still at a significant risk of life-threatening ART initiation [incidence rate ratio (IRR) 2.35, 95% CI opportunistic infections (CD4 < 200 cells/ml) after 1.29–4.31; P ¼ 0.006], and in those with CD4 cell count 12 months of treatment, showing that room for nadir less than 50 cells/ml (IRR 1.73, 95% CI 0.91–3.29; improvement exists even for second-line therapy.
P ¼ 0.09) Interestingly, the number of NRTIdrugs changed (P ¼ 0.39), level of CD4 cell count at We found that overall a relatively small proportion of switch (P ¼ 0.26), and type of protease inhibitor (boosted patients, after at least 6 months on ART in MSF versus nonboosted; P ¼ 0.31) were not significant programmes, switched to a second-line regimen for predictors of survival in this analysis.
treatment failure (switch rate 4.8/1000 person-years; 6%of cohort at 48 months). Switch rates to second-linetherapy were lowest in sub-Saharan patients and highestin Eastern Europeans, probably reflecting differences in access to viral load and CD4 testing in those contexts(many MSF projects in Africa are based in rural areas).
In this first published study of second-line ART in RLS, Our observed switch rate probably reflects only the most we have shown encouraging early treatment outcomes, obvious cases of treatment failure, due to our inability to with clinical and immunological outcomes similar to accurately diagnose when a first-line regimen should be those published for first-line regimens in RLS changed to second line. This is also suggested by ourfinding of lower survival in patients switched to second- Table 4. Number of patients and incidence of deaths or lost to line therapy compared with those who did not, suggesting follow-up by switch status, Me´decins Sans Frontie`res, HIV cohort that late diagnosis of failure would increase the risk of death in patients started on second-line ART. In the absence of routine virological monitoring in our programmes, diagnosis of failure is usually based on either the occurrence of a clinical event, or on immunological criteria as per WHO guidelines These data from a large number of RLS highlight the increased need for second-line therapy in similar settings.
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Table 5. Factors and incidence of death or lost to follow-up of patients achieving early immunological success on second-line antiretroviraltreatment (ART), Me´decins Sans Frontie`res HIV cohort 2001–2006, 26 countries.
CI, confidence interval; IRR, incidence rate ratio from Poisson regression adjusted for geography (sub-Saharan Africa, Asia, Latin America); IRRa,incidence rate ratio from Poisson regression adjusted for geography, CD4 nadir counts, and WHO stage 4 at ART start; NRTI, nucleoside reversetranscriptase inhibitor; PI, protease inhibitor. P value from likelihood ratio test.
Evidence of the efficacy of rescue regimens has been immunological or clinical methods Although not a shown in studies conducted in resource-rich settings, RLS, our ART programme in Khayelitsha, South Africa, where median CD4 cell count at second-line initiation is routinely measures patient viral load (and CD4 cell count) higher, viral load monitoring routinely performed, and at baseline and 3 and 6 months after the start of treatment, as treatment options readily available. In a European study well as every 6 months thereafter As costs and conducted before the widespread availability of technological limitations decrease for viral load testing genotyping, patients initiating a second protease inhibitor , its use in RLS could beneficially increase switching to regimen at lower viral load with higher CD4 cell counts, second-line therapy while optimizing the duration of first- or receiving additional nucleosides, were more likely to line regimens. Ideally, treatment-failure algorithms achieve undetectable viral loads. Studies in South Africa could be designed based on diagnostic parameters, such as where viral load is routinely measured and viral load, CD4 cell count, or haemoglobin levels, and treatment failure is defined as two consecutive viral load incorporated into HIV treatment guidelines in the field.
measurements more than 5000 copies/ml, reported thatafter 36 months of NNRTI-based first-line therapy, 5.6 to In RLS, constraints at the treatment level also negatively 11.9% of patients switched to a second-line regimen.
affect therapy outcomes. Even in the presence ofvirological failure, clinicians working in RLS may be Although the number of initially naive patients switched to reluctant to change to second-line regimens, as shown in second line in our study was small, in RLS there is an one of the before-mentioned South African studies .
increasing need for second-line ART regimens as ART Evidence shows that clinical and immunological benefits cohorts mature and access to virological monitoring can be obtained on a virologically failing regimen, but this increases Detection of early treatment failure will effect has been demonstrated only in patients on a protease ensure that patients are able to switch regimens before the inhibitor-based regimen Prices of second-line drugs occurrence of severe clinical events and will prevent have been reported to be about ten times higher than first- unnecessary early switches. One major strategy for line agents . Also, concerns exist about the limited improving the diagnosis of first-line treatment failure in efficacy of available second-line regimens involving RLS is to increase viral load monitoring. In the absence of boosted and nonboosted protease inhibitors or the addition regular viral load monitoring, diagnosis of treatment failure of a single new NRTI. Clinicians often also doubt the might be delayed due to reliance on less sensitive immediate benefit of second-line therapy because of the Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Second-line antiretroviral therapy Pujades-Rodrı´guez et al.
difficulties in ensuring patient treatment adherence due to extrapolated to patients who might have received first-line the high pill burden of protease inhibitor-containing regimens prior to entry in the MSF cohort.
regimens, absence of fixed-dose drug combinations, needfor refrigeration, and necessary meal restrictions. Finally, Unsurprisingly, we showed that severe immunosuppres- the fear that no further treatment options will be available if sion at baseline for first-line ART, and the history of a subsequent failure on second-line regimens occurs might severe clinical event (WHO stage 3 or 4), increased the risk of mortality on second-line treatment. Our findingsthus stress the need to enable access to first-line ART In our study more than half of the patients were put before severe immunosuppression has developed, rein- on NFV-based regimens, due to a lack of refrigeration forcing the need to scale up early access to HIV testing systems and heat-stable boosted protease inhibitors, which are less effective than a regimen containing aritonavir-boosted protease inhibitor. Also, the choices In summary, we report a relatively low rate of switch to for replacing the NRTI drugs were limited due to a second-line HIV treatment in ART-naive adults in MSF restricted formulary of drugs. Despite these constraints, programmes in RLS, but good early outcomes on second- our results showed that rescue following the failure of line therapy. Severe immunosuppression at first-line ART WHO-recommended first-line treatment (including the initiation increased mortality on second-line treatment.
regimen d4T/3TC/NVP) is feasible and efficient in Considering the success of patients put on a second-line RLS, at least in MSF programmes. Therefore, in addition regimen, improving the tools to efficiently diagnose first- to improving the diagnosis of treatment failure, the line treatment failure, and clearing the hurdles of access obstacles to second-line drug access and usage must be and adherence to more effective drug regimens, are addressed by reducing costs, increasing the availability of critical actions that should be taken to allow more patients newer, more potent molecules (including heat-stable in RLS to benefit from second-line HIV therapy.
formulations of boosted protease inhibitors), andfacilitating adherence through fixed-dose formulationsthat do not require food restrictions.
Less than 2% of patients eligible for the study wereexcluded from the analyses because of unknown age, and We thank the ministries of health of all the countries, the this percentage was similar across continents. We MSF field teams, and the patients, for providing the data recognize, however, several limitations in our study. First, for this analysis. Our thanks to the MSF AIDS Working it was based on monitoring data from a multicentric Group for their comments and Oliver Yun for his observational cohort, and the reason for switch to second editorial support on the manuscript.
line was not recorded prospectively. Therefore, we cannotcompletely exclude that some of the switches in therapywere in fact antiretroviral drug replacements due to reasonsother than treatment failure, such as drug toxicity. We are, however, confident that the majority of patients eligible forthis analysis were true treatment failures, as 62% had at least 1. Calmy A, Pinoges L, Szumilin E, Zachariah R, Ford N, Ferradini L. Medecins Sans Frontieres. Generic fixed-dose combination one of the WHO criteria for treatment failure recorded, antiretroviral treatment in resource-poor settings: multicentric and our definition of second-line therapy (changes of both observational cohort. AIDS 2006; 20:1163–1169.
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