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Clinical Science

Discordant Responses to Potent Antiretroviral Treatment in Previously Naive HIV-1-Infected Adults Initiating Treatment in Resource-Constrained Countries

The Antiretroviral Therapy in Low-Income Countries (ART-LINC) Collaboration

Tuboi, Suely H, MD*; Brinkhof, Martin W G, PhD; Egger, Matthias, MD, PhD; Stone, Roslyn A, PhD; Braitstein, Paula, PhD; Nash, Denis, PhD§; Sprinz, Eduardo, MD; Dabis, François, MD, MPH; Harrison, Lee H, MD*; Schechter, Mauro, MD, PhD#

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2007 - Volume 45 - Issue 1 - p 52-59
doi: 10.1097/QAI.0b013e318042e1c3
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Abstract

In high-income countries, the availability of highly active antiretroviral therapy (HAART) has led to major reductions in morbidity and mortality from HIV infection.1-3 Several studies in this setting have demonstrated a stronger correlation between long-term prognosis and virologic response (VR) and immunologic response (IR) after 6 months on HAART than with baseline values.4-6 In general, the initiation of HAART leads to a significant reduction in HIV plasma viral load (PVL) and an increase in CD4 cell count.7,8 Some patients on HAART exhibit a pattern of sustained CD4 cell response despite persistent viremia or do not exhibit a significant rise in CD4 cell count despite viral suppression, however. Both situations are referred to as discordant responses and have been consistently associated with an intermediate risk of developing an AIDS event or death in developed countries.9-12

In high-income countries, discordant responses have been reported to occur in 20% to 30% of patients 6 months to 2 years after starting HAART.4,9,13-16 In developing countries, the effectiveness of HAART in suppressing viral replication and inducing a rise in CD4 cell counts is comparable to what has been reported from developed countries.17-22 Nonetheless, to date, there is scant information on the frequency and prognostic significance of discordant responses to HAART in low-income countries, where patients often start therapy at advanced stages of immune deficiency and frequently have comorbidities that may impair their response to therapy.23

We report on the frequency of and risk factors for discordant responses at 6 months on HAART in previously treatment-naive HIV patients in resource-limited countries.

METHODS

Patients and Measurements

The Antiretroviral Therapy in Low-Income Countries (ART-LINC) Collaboration is a network of HIV treatment programs in Africa, Latin America, and Asia. The ART-LINC Collaboration has been described previously.24,25 The selection of patients and data extraction were done at the participating sites. Data were anonymized locally and then pooled and analyzed centrally. At all sites, local ethics committees or institutional review boards approved the collection of data.

Only sites that collected HIV PVLs routinely were included in the analysis. All previously treatment-naive individuals who initiated therapy between March 1996 and April 2004, had a known date of therapy initiation, were aged 16 years or older, and had a documented CD4 cell count at baseline were included in this analysis.

The type of HAART regimen was defined as protease inhibitor (PI) based (1 PI + 2 nucleoside reverse transcriptase inhibitors [NRTIs], including ritonavir-boosted regimens), nonnucleoside reverse transcriptase (NNRTI) based (1 NNRTI + two NRTIs), or a nonstandard HAART regimen (including triple-NRTI regimens and any other regimen containing a minimum of 3 drugs). The stage of disease was classified as less (Centers for Disease Control and Prevention [CDC] stage A/B, World Health Organization [WHO] stage I or II) or more advanced (CDC stage C, WHO stage III or IV). The baseline CD4 cell count and HIV PVL were measured at therapy initiation (−180 or 7 days).

Study Outcomes and Statistical Analysis

VR was defined as achieving a plasma HIV PVL <500 copies/mL, whereas IR was defined as an increase of at least 50 CD4 cells/μL at 6 months. Measurements closest to 6 months after starting HAART, within 3 to 9 months, were used in these analyses. Outcomes were defined as complete response (VR+IR+), virologic-only response (VR+IR), immunologic-only response (VRIR+), and nonresponse (VRIR). An intent-to-continue-treatment approach, which ignored subsequent therapy changes or interruptions, was used. Between-group comparisons were made by using the χ2 test for categoric variables and the Kruskall-Wallis test for continuous variables. A multinomial logistic regression model was fit to assess the relation between baseline characteristics and the 6-month outcomes. Heterogeneity introduced by different sites was accounted for by including site as a fixed effect in the model, and Huber-White robust SEs were calculated to account for intrasite correlation.

Missing baseline information on stage of disease and PVL were multiply imputed, based on whether the patient died, site, CD4 cell count, gender, age, and type of HAART regimen. In these imputations, values of the missing data were randomly sampled from their predicted distributions. Analyses were run on each of 20 data sets that included the imputed values, and the results were combined with the rules of Rubin.26 Analyses were performed using STATA version 9.0 (Stata Corporation, College Station, TX).

RESULTS

During the study period, 4810 patients initiated HAART. Of these, 158 (3.2%) died within 6 months of therapy and 1541 (32.0%) were from sites where the viral load was not routinely measured, and thus were not included in the analysis. The demographic and clinical characteristics of the remaining 3111 patients are shown in Table 1 according to IRs and VRs at 6 months on therapy. Approximately half were male (50.9%), with a median age at HAART initiation of 35 years. The median baseline CD4 cell count and HIV RNA PVL were 137 (interquartile range [IQR]: 49-240) cells/μL and 5.1 (IQR: 4.6-5.6) log10 copies/mL, respectively; 1591 (51.1%) had more advanced disease, and 1783 (57.3%) were prescribed an NNRTI-based regimen. Excluded patients were more likely to be female (55% vs. 45%; P < 0.01) and to have a lower baseline CD4 cell count (70 vs. 136 cells/μL; P < 0.01).

TABLE 1
TABLE 1:
Patients' Baseline Characteristics According to IR and VR at 6 Months of Therapy and Comparison Between Those With Known and Unknown Responses

Most patients (57.3%) started therapy with an NNRTI-based regimen, and 29% started with a PI-based regimen. The most frequently prescribed NNRTIs and PIs were efavirenz (66.1%) and indinavir (48.8%), respectively. PI-based regimens were more commonly prescribed before 2000 (64.0%). From 2000 onward, NNRTI-based regimens predominated (76.0%).

Recipients of nonstandard HAART regimens had the highest median baseline CD4 count (185 [IQR: 63-315] cells/μL), whereas recipients of PI-based and NNRTI-based regimens had similar median baseline counts (131 [IQR: 45-253] cells/μL and 131 [IQR: 48-222] cells/μL, respectively). The baseline PVLs for recipients of NNRTI-based, PI-based, and nonstandard regimens were 5.1 (IQR: 4.6-5.6) log10 copies/mL, 5.2 (IQR: 4.7-5.7) log10 copies/mL, and 4.9 (IQR: 4.5-5.5) log10 copies/mL, respectively (data not shown).

Immunologic and Virologic Responses at 6 Months of Therapy

At 6 months on therapy, 1914 (61.5%) patients had information on PVLs and CD4 cell counts. For 1197 (38.5%), the outcome could not be ascertained because of missing data on PVLs or CD4 cell counts. Among these patients, 292 (24.4%) were lost to follow-up at 6 months.

Among the patients with available information, 1074 (56.1%) were complete responders, 364 (19.0%) were virologic-only responders, 283 (14.8%) were immunologic-only responders, and 193 (10.1%) were nonresponders (Table 2). The overall VR rate was 75.1%, the median increase in CD4 count was 106 (IQR: 40-178) cells/μL, and the median viral load reduction was 2.8 (IQR: −3.4 to −1.9) log10 copies/mL. Complete responders showed the greatest CD4 cell count increases and PVL decreases, and nonresponders showed the smallest changes in these measurements.

TABLE 2
TABLE 2:
Outcomes at 6 Months of Therapy for 1914 Patients With Known Outcome

Table 3 shows the results of the multinomial logistic regression model for 1914 patients with a known response, with complete responders as the reference group, controlling for demographic and clinical variables, calendar year, and participating site. There were no significant differences by gender between complete responders and all other categories of response.

TABLE 3
TABLE 3:
Odds Ratios and 95% Confidence Intervals of Discordant Responses Relative to Complete Responses in 1914 Patients With Known Outcomes*

In comparison to complete responders, virologic-only responders were significantly more likely to be older than 50 years of age, to have a baseline CD4 count >99 cells/μL, or to have received nonstandard HAART regimens and were less likely to have a baseline HIV RNA PVL >100,000 copies/mL (see Table 3).

Patients who showed an immunologic-only response were less likely than complete responders to be older than 30 years of age and to have a baseline CD4 count >99 cells/μL and were more likely to have a baseline HIV RNA PVL >100,000 copies/mL or to have received a PI-based regimen (see Table 3). The probability of having an immunologic-only or nonresponse rather than a complete response decreased after 2000 (data not shown).

Some covariates had opposite effects on the 2 categories of discordant responses. Increasing age, increasing baseline CD4 cell count, and other regimens were positively associated with virologic-only responses, and PI-based regimens were positively associated with immunologic-only responses, whereas a baseline HIV RNA PVL ≥100,000 copies/mL was negatively associated with virologic-only responses and positively associated with immunologic-only responses. Figure 1 shows the adjusted odds ratios of discordant responses by baseline CD4 cell count strata, with complete responders as the reference group.

FIGURE 1
FIGURE 1:
Adjusted odds ratios of responses (in log scale) after 6 months of HAART relative to complete response by baseline CD4 cell count.

We assessed the extent to which the rate of unknown response could have introduced bias in our analysis by comparing baseline characteristics and VRs and IRs between patients with known and unknown responses at 6 months. Patients with known and unknown responses at 6 months did not differ with respect to gender, age, or baseline CD4 cell count (see Table 1). Patients with unknown responses were more likely to have received an NNRTI-based regimen and to have an unknown baseline PVL and stage of disease. At 6 months of therapy, however, patients with an unknown response who had available information on VR or IR (but not both) had overall similar median changes in CD4 cell counts and PVLs as patients with both responses known (112 vs. 105 cells/μL, P = 0.26; and −2.7 vs. −2.8 log10 copies/mL, P = 0.88, respectively). A multinomial model that included a missing outcome category led to similar results, supporting the hypothesis that this subgroup of patients did not significantly differ from the 1914 patients with known outcomes.

DISCUSSION

To our knowledge, this is the first report on the frequency of and risk factors for discordant responses in a large cohort of patients initiating HAART in low-income countries. The encountered frequency of a discordant response (33.8%) at 6 months of therapy is similar to what has been reported from high-income countries.10,11,14-16 We have found that compared with complete responders, virologic-only responders were older, had higher baseline CD4 cell counts, had lower baseline PVLs, and were more likely to have received a nonstandard HAART regimen and that immunologic-only responders were younger, had lower baseline CD4 cell counts, and were more likely to have received a PI-based or nonstandard regimen.

Our finding of older age being associated with a virologic-only response and inversely associated with an immunologic-only response is consistent with studies conducted in high-income countries10-12,27 and the hypothesis that the magnitude of immune restoration is dependent on thymic activity, which decreases with age.28 Other reports from high-income countries have also demonstrated that older age is independently associated with impaired IRs despite sustained VRs.29 It is also suggestive of better adherence among older patients, in agreement with other studies.30,31

As in reports from high-income countries, a higher baseline CD4 cell count was associated with an increased probability of a virologic-only response and with a reduced probability of an immunologic-only response.10,11,32 One possible explanation for this finding is the nonlinear nature of CD4 cell count increases after HAART initiation across the different baseline CD4 count strata. In agreement with the findings of Moore et al,11 our results also suggest that increases in CD4 counts after initiation of therapy might be greater in individuals with lower CD4 cell counts at therapy initiation. A baseline PVL greater than 100,000 copies/mL was associated with a lower probability of having a virologic-only response, a finding also reported in the studies of Moore et al11 and Nicastri et al.10

Our analysis showed that immunologic-only responders were 1.6 times more likely than complete responders to have received PI-based regimens rather than NNRTI-based regimens. This finding has to be interpreted with caution, however. As noted previously, differences in response between HAART regimens in this observational study are likely to be subject to selection by indication bias. Nonetheless, it has been suggested that the additional effect of PIs on the IR could be attributable to their ability to reduce T-cell apoptosis.13 A superior IR to PIs compared with NNRTIs was suggested among virologic responders33 but not among patients showing a discordant response.11,27,34 This issue is unlikely to be fully elucidated by observational studies.

Qualitative differences in the effects of predictors of the 2 types of discordant responses support the hypothesis of different underlying mechanisms. Although the long-term clinical outcomes seem to be comparable,11 identifying risk factors for both types of early discordant response may lead to specific preventive strategies for each type.

Discordant responses have been associated with increased risk of clinical progression and mortality in developed countries. In a cohort of antiretroviral-experienced patients with advanced HIV disease who started PI-based HAART and were followed for longer than 30 months, discordant responders at 12 months experienced significantly more AIDS-defining events than full responders, with immunologic-only responders having a slightly higher probability of being event-free compared with virologic-only responders.27 In another study involving more than 2100 antiretroviral-experienced and -naive HIV patients followed for a median of 44 months, immunologic-only and virologic-only responders had a significantly lower risk of clinical progression than nonresponders but 2.3- and 1.9-fold greater risks of death or new AIDS-defining events than complete responders, respectively.10

Little is known about the mechanisms underlying the development of discordant responses, but they are apparently dependent on the interaction of a multitude of viral and host factors. One hypothesis is that HAART selects viral strains that are less fit, which, in turn, results in reduced pathogenicity of drug-resistant viruses. In fact, it has been shown that recipients of PI-based regimens with prolonged discordance (immunologic success despite virologic failure) have decreased viral replication capacity.35-37 In a closely followed cohort of HAART-naive patients for whom repeated measures over a period of 1 year were analyzed, almost all patients who showed a discordant IR at 1 year had had a prior transient period of undetectable PVL or partial suppression of PVL to <1000 copies/mL, suggesting that partial viral suppression is the primary mechanism involved in discordant CD4 cell count increases.29 Genetic variability, such as polymorphisms associated with drug transportation38 and T-lymphocyte apoptosis,39,40 has been implicated in the pathogenesis of the virologic-only response. In addition, the concomitant use of tenofovir and didanosine has been shown to cause an impaired IR.41,42 In the ART-LINC Collaboration, the negligible proportion of patients initiating therapy with this combination is not likely to have influenced our results.

A major strength of the present study is the large number of previously antiretroviral-naive patients starting therapy with NNRTI-based regimens. Most studies published so far have been conducted in developed countries and have included experienced patients receiving PI-based regimens; these patients are not representative of patients starting therapy in resource-limited settings, where most start treatment with NNRTI-based regimens.24,25

Our study has several limitations. First, this study did not address the impact of adherence on outcomes. In the study of Moore et al,11 suboptimal adherence was predictive of virologic-only and immunologic-only responses rather than complete response. Second, additional variability may have been introduced as a result of differences in population genetics or infecting HIV subtypes, which were not considered in the present analysis. Third, patients prescribed NNRTIs had lower plasma HIV RNA levels and higher CD4 cell counts than patients prescribed PIs, highlighting the importance of provider bias in determining differences between different regimens.43 Fourth, we acknowledge that the 38% unknown response rate could potentially affect our results. Our analysis showed that this group of patients did not differ significantly from the patients in the other categories of response with respect to major baseline risk factors, however. We believe that the availability of laboratory resources on-site or other factors that limited access to laboratory tests were determinants of this response pattern rather than patient characteristics. In addition, including patients with an unknown response at 6 months did not substantially change the estimates in the final model. Finally, if the limited availability of resources caused programs to prioritize monitoring VRs and IRs in patients who did not seem to be doing well clinically, we could have underestimated the virologic and immunologic effectiveness of HAART in these settings.

Our results add to accumulating data on response to therapy in resource-limited countries and may have important public health implications. We showed that despite considerable differences in disease severity at presentation and baseline CD4 cell counts of patients in resource-limited settings, the frequency of and risk factors for discordant response are similar to those observed in developed countries. In these countries, higher mortality has increasingly been reported for discordant responders than for complete responders. Clinical management of these patients often requires a more sophisticated laboratory approach (genotypic and phenotypic resistance) and the availability of second-line therapy. Data on the frequency of this phenomenon and identification of its risk factors are of prime importance and may help HIV/AIDS programs to plan their laboratory and therapeutic resources. Further studies are needed to assess the long-term impact of early discordant responses in these resource-limited countries.

ACKNOWLEDGMENTS

The authors are grateful to Jack Whitescarver, Michel Kazatchkine, and Brigitte Bazin for their encouragement and support. The authors also thank all the patients and collaborating center staff who made this project possible as well as Margaret May, Jonathan Sterne, Lotti Senn, Raffaele Battaglia, Gian Tony, and Sophie Lamarque for ongoing help and advice.

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APPENDIX

Antiretroviral Therapy in Low-Income Countries Collaboration

  • Writing Committee: Suely H. Tuboi, Martin Brinkhof, Mathias Egger, Roslyn A. Stone, Paula Braitstein, Denis Nash, Eduardo Sprinz, François Dabis, Lee H. Harrison, and Mauro Schechter
  • Principal Investigators: François Dabis, Matthias Egger, and Mauro Schechter
  • Central Team: Eric Balestre, Paula Braitstein, Martin Brinkhof, and Catherine Seyler
  • Steering Group: Kathy Anastos (Kigali, Rwanda), Franck-Olivier Ba-Gomis (Abidjan, Côte d'Ivoire), David Bangsberg (Mbarara/Kampala, Uganda), Andrew Boulle (Cape Town, South Africa), Jennipher Chisanga (Lusaka, Zambia), Eric Delaporte (Dakar, Senegal), Diana Dickinson (Gaborone, Botswana), Ernest Ekong (Lagos, Nigeria), Kamal Marhoum El Filali (Casablanca, Morocco), Mina Hosseinipour (Lilongwe, Malawi), Charles Kabugo (Kampala, Uganda), Silvester Kimaiyo (Eldoret, Kenya), Mana Khongphatthanayothin (Bangkok, Thailand), N. Kumarasamy (Chennai, India), Christian Laurent (Yaounde, Cameroon), Ruedi Luthy (Harare, Zimbabwe), James McIntyre (Johannesburg, South Africa), Timothy Meade (Lusaka, Zambia), Eugene Messou (Abidjan, Côte d'Ivoire), Denis Nash (New York, NY), Adama Ndir (Dakar, Senegal), Winstone Nyandiko Mokaya (Eldoret, Kenya), Margaret Pascoe (Harare, Zimbabwe), Larry Pepper (Mbarara, Uganda), Papa Salif Sow (Dakar, Senegal), Sam Phiri (Lilongwe, Malawi), Mauro Schechter (Rio de Janeiro, Brazil), John Sidle (Eldoret, Kenya), Eduardo Sprinz (Porto Alegre, Brazil), Besigin Tonwe-Gold (Abidjan, Côte d'Ivoire), Siaka Toure (Abidjan, Côte d'Ivoire), Stefaan Van der Borght (Amsterdam, The Netherlands), Ralf Weigel (Lilongwe, Malawi), and Robin Wood (Cape Town, South Africa)
  • Advisory Committee: Zackie Achmat, Chris Bailey, Kevin de Cock, Wafaa El-Sadr, Ken Freedberg, Helene Gayle, Charlie Gilks, Catherine Hankins, Tony Harries, Elly Katabira, Jonathan Sterne, and Mark Wainberg
  • Funding: National Institutes of Health Office of AIDS Research (Paolo Miotti and Jack Whitescarver), Agence Nationale de Recherche sur le Sida (ANRS) (Brigitte Bazin), and Canadian Institutes of Health Research (CIHR)
  • Collaborating Centers: CEPREF/ANRS COTRAME (Abidjan, Côte d'Ivoire), Centre Hospitalier Universitaire (Casablanca, Morocco), CESAC (Bamako, Mali), CIRBA (Abidjan, Côte d'Ivoire), CORPMED (Lusaka, Zambia), DARVIR (Douala, Cameroon), Heineken International (Amsterdam, The Netherlands), HIVNAT (Bangkok, Thailand), Hospital de Clinicas/SOBRHIV (Porto Alegre, Brazil), Hospital Universitario Clementino Fraga Filho (Rio de Janeiro, Brazil), Independence Surgery Clinic (Gaborone, Botswana), Innovir Institute (Johannesburg, South Africa), ISAARV/ANRS (Dakar, Senegal), Kamuzu Central Hospital/Lighthouse Trust (Lilongwe, Malawi), Makerere-University of California, San Francisco/Generic Antiretroviral Therapy Project (Kampala, Uganda), Military Reference Hospital (Lagos, Nigeria), Moi University College of Health Sciences/University of Indiana (Eldoret, Kenya), Nsambya Hospital (Kampala, Uganda), PARVY/Military Hospital, Médecins Sans Frontières and Institut de Recherche pour le Développement (Yaoundé, Cameroon), PHRU/Opera (Soweto, South Africa), University of Cape Town/CTAC (Cape Town, South Africa), University of Cape Town/Khayelitsha (Cape Town, South Africa), and YRG Care (Chennai, India)
Keywords:

antiretroviral therapy; CD4 lymphocyte count; viral load; discordant; low-income population; treatment outcome

© 2007 Lippincott Williams & Wilkins, Inc.