JAIDS Journal of Acquired Immune Deficiency Syndromes:
Resistance to Antiretroviral Drugs in Treated and Drug-Naive Patients in the Democratic Republic of Congo
Muwonga, Jérémie MD*†; Edidi, Samuel MSc*; Butel, Christelle MSc‡; Vidal, Nicole PhD‡; Monleau, Marjorie PhD‡; Okenge, Augustin MD§; Mandjo, Jean Lambert MD§; Mukumbi, Henry MD‖; Muyembe, Jean Jacques MD†; Mbayo, Ferdinand MD†; Nzongola, Donatien Kayembe MD†; Delaporte, Eric MD, PhD‡; Boillot, François MD¶#; Peeters, Martine PhD‡
From the *AIDS National Reference Laboratory (LNRS), General Hospital of Kinshasa, Kinshasa, Democratic Republic of Congo; †Department of Medical Biology, University of Kinshasa, Kinshasa, Democratic Republic of Congo; ‡UMI 233, Institut de Recherche pour le Developpement (IRD) and University of Montpellier 1, Montpellier, France; §AIDS National Control Program (PNLS), Kinshasa, Democratic Republic of Congo; ‖AMO-Congo, Democratic Republic of Congo; ¶Alter-Santé Internationale & Développement, Montpellier, France; and #International Union against Tuberculosis and Lung Diseases, Paris, France.
Supported by the Integrated HIV Care for Tuberculosis Patients Living with HIV/AIDS project of the International Union against Tuberculosis and Lung Diseases, through a grant from the European Commission (SANTE 2004/078/547/1).
The authors have no conflicts of interest to disclose.
Correspondence to: Martine Peeters, PhD, Laboratoire Retrovirus, UMI 233, Institut de Recherche pour le Developpement (IRD), BP 64501, 34394 Montpellier Cedex 1, France (e-mail: email@example.com).
Background: We studied virological outcome and drug resistance in patients on antiretroviral therapy (ART) in health care centers in the Democratic Republic of Congo and looked for the presence of drug resistance in antiretroviral-naive patients attending the same clinics.
Methods: In 2008, we conducted a cross-sectional survey among patients on ART for ≥12 months in 4 major cities [Kinshasa (n = 289), Matadi (n = 198), Lubumbashi (n = 77), and Mbuji-Mayi (n = 103)]. Genotypic drug resistance tests were done with an in-house assay on samples with viral load >1000 copies/mL. ART-naive patients (n = 283) were also consecutively enrolled in the same clinics.
Results: Of the 667 patients on ART, >98% received Lamivudine + Stavudine/azidothymidine + Nevirapine/Efavirenz as first-line regimen and 74.4% were women. Median time on ART was 25 months [interquartile ratio (IQR), 19-32] in Kinshasa, 26 months (IQR, 19-32) in Matadi, 27 months (IQR, 19-44) in Lubumbashi, and 19 months (IQR, 16-24) in Mbuji-Mayi. A total of 97 patients (14.6%) had viral load >1000 copies/mL, and among the 93 successfully sequenced samples, 78 (83.9%) were resistant to at least 1 drug of their ART regimen: 68 harbored resistance mutations to nucleoside reverse transcriptase inhibitor (NRTI) and nonnucleoside reverse transcriptase inhibitor (NNRTI), 2 to NRTI only, 7 to NNRTI only, and 1 to NRTI + NNRTI + protease inhibitor. The majority of patients, 70/78 (89.7%), were resistant to at least 2 of the 3 drugs from their treatment. The use of next-generation NNRTI, etravirine was already compromised for 19.2% (15/78) of the patients and 7 patients had the K65R mutation compromising the use of tenofovir in second-line regimens. The proportion of antiretroviral-resistant patients increased over time from 8.4% to 18.6% for patients on ART for 12-23 months or >35 months (P = 0.013), respectively. Virological failure and rates of drug resistance were significantly higher among men than women, 19.9% versus 8.8%, respectively (P = 0.0001). Among the 253 recently diagnosed patients, 20 (7.9%) harbored resistance mutations.
Conclusions: The accumulation of drug resistance mutations with time on ART needs further attention, and surveillance should be reinforced in ART programs in sub-Saharan Africa.
The government of the Democratic Republic of Congo (DRC) became one of the first in Africa to endorse a national policy for HIV/AIDS prevention and control in the early 80s, and it committed support to basic research and epidemiological studies through Project SIDA.1 The political crisis, which accelerated in the early 1990s, led to a highly disorganized political and social environment, resulting in evacuation of all foreign staff and withdraw of foreign funding. Subsequently, the country has experienced an internal armed conflict involving 6 foreign armed forces between 1998 and 2002.2 These conflicts have led to profound socioeconomic changes and the long period of civil unrest has damaged the health care delivery system. The health sector's ability to respond to the needs of the citizens of the DRC has declined significantly over the past decades, and it is estimated that 70% of the population has little or no access to health care, including HIV/AIDS services.3 However, with the end of hostilities, the country renewed commitment to the fight against HIV/AIDS. In 2005, a national strategic plan for scaling up access to antiretroviral therapy (ART) was developed. Today, under the leadership of the National AIDS Control Programme, many international partners and nongovernmental organizations (NGOs) and local community-based organizations provide care and support to people living with HIV/AIDS. Since 2002, the ART coverage increased and is estimated to reach 20%-30% of patients with CD4 counts <200 cells/mm3 in 2008.4 To facilitate the rapid expansion of access to ART, the country adopted the standardized World Health Organization (WHO) public health approach, which recommends treatment initiation and switch guided by clinical disease progression and where possible with CD4 cell counts. The recommended standardized first-line ART regimens use a combination of 2 nucleoside reverse transcriptase inhibitors [NRTIs; Lamivudine (3TC) + azidothymidine (AZT)/Stavudine (d4T)] and 1 nonnucleoside reverse transcriptase inhibitor [NNRTI; Efavirenz (EFV)/Nevirapine (NVP)].5
One of the major potential challenges of the widespread use of antiretroviral (ARV) drugs in Africa without biological monitoring is the risk of emergence of ARV drug-resistant HIV strains because treatment failure is recognized after virological failure thus allowing the accumulation of drug resistance mutations.6,7 With the absence of individual patient monitoring for viral load and drug resistance, sentinel studies for surveillance of drug resistance in ART-naive patients and emergence of mutations in patients on ART should be done to inform health authorities on the efficiency of first- and second-line ART and adapt recommendations on future ART strategies.8
The DRC, in Central Africa, is the second largest country on the continent with a total population of ∼60 million inhabitants, of whom 50% live in rural areas. In addition to deficiencies in health system and lack of resources, the country size and lack of road infrastructure and communication between different areas are an additional challenge to ART scaling up. Here we describe in 4 major cities in DRC, virological outcome, and emergence of drug resistance in a cross-sectional survey among HIV-1-infected patients, treated according to the national guidelines in clinics of AMO-Congo, which is the main Congolese NGO specialized in HIV/AIDS work. In the same clinics, we analyzed also HIV-1 strains from ART-naive patients for the presence of drug resistance mutations.
A cross-sectional survey was conducted at outpatient clinics depending on the NGO AMO-Congo operating in 4 major cities (3 clinics in Kinshasa and 1 in Matadi, Lubumbashi, and Mbuji-Mayi) of DRC. Only in Mbuji-Mayi patients were recruited at the NGO clinic and at the public hospital. All study sites provided ART according to the national guidelines for ART scale-up and were chosen to allow enrollment of sufficient eligible patients, as recommended by WHO surveillance and monitoring surveys, during a 2-month period.8 During September and October 2008, patients receiving first-line ART for at least 12 months were consecutively enrolled. After informed consent was obtained, a standardized questionnaire was administered to assess demographic, epidemiologic, clinical, and treatment information and 10 mL of whole blood was collected on EDTA tubes. After centrifugation, plasma aliquots were frozen at −80°C. ART-naive patients were also enrolled during the same period at the same study sites.
HIV-1 RNA Viral Load and Genotypic Drug Resistance Testing
Plasma viral load was measured with the Generic viral load assay (Biocentric, Bandol, France), with a detection limit of 300 copies/mL.9 Genotypic drug resistance testing was performed on samples with HIV-1 RNA levels ≥1000 copies/mL using a previously described in-house assay.10 Briefly, viral RNA was extracted from the plasma using the QIAamp Viral RNA kit (Qiagen, Courtaboeuf, France). RNA was transcribed into cDNA with the reverse primer IN3, cDNA was amplified by a nested polymerase chain reaction using the Expand High Fidelity PCR system (Roche, Meylan, France) with outer primers G25REV and IN3 and inner primers AV150 and polM4. The amplified fragments covering the protease (amino acids 1-99) and reverse transcriptase (amino acids 1-310) were purified with the QIAquick Gel Extraction kits (Qiagen) and directly sequenced using the BigDye Terminator v3.1 Cycle Sequencing kit (Applied Biosystems, Carlsbad, CA). The sequences were assembled with the SeqMan II software (DNASTAR, Madison, WI). Amino acid sequences were analyzed for the presence of mutations in protease and reverse transcriptase genes with the drug resistance interpretation algorithm from ANRS (version July 2010) (http://www.hivfrenchresistance.org/).
To identify HIV-1 drug resistance mutations in strains from ART-naive patients, nucleotide sequences were translated into amino acid sequences that were then inspected to identify transmitted drug resistance mutations based on the WHO list of mutations recommended for epidemiological studies.11 HIV-1 subtypes/circulating recombinant forms were determined by phylogenetic tree and recombination analysis as previously decribed.12
Between September and October 2008, a total of 667 HIV-positive patients receiving ART for at least 12 months were consecutively enrolled in the study (Table 1). The majority of the patients were women [496 (74.4%)], and the median age of women was slightly lower than for men, that is, 42 years [interquartile ratio (IQR), 35-49] versus 46 years (IQR, 40-50). In all study sites, more women than men were enrolled and their median ages were comparable across the 4 sites, except for Mbuji-Mayi were the median age of women was lowest. Almost all patients, 656/667 (98.4%) received 3TC + d4T/AZT + EFV/NVP as first-line treatment with only 77 (11.5%) patients having AZT and 59 (8.9%) having EFV in their drug regimen. One hundred fourteen (17.1%) patients reported treatment interruption or switch. Switch concerned mainly replacement of d4T by AZT or NVP by EFV and only 7 switched to protease inhibitor (PI) regimens. Overall, the median time on ART was 25 months (IQR, 19-32) in Kinshasa, 26 (IQR, 19-32) in Matadi, 27 (IQR, 19-44) in Lubumbashi, and 1913-21 in Mbuji-Mayi (IQR, 16-24).
Among the 667 patients, 129 (19.3%) had plasma HIV RNA levels above the detection limit of the viral load test, that is, >300 copies/mL, and were therefore defined as viremic on ART. Virological failure ranged between 17.3% and 22.2% across the 4 sites (Table 1). Although not significant, the proportion of patients with virological failure increased with time on ART, going from 16.5% (53/321) for patients who received ART between 12 and 23 months, to 19.8% (46/233) for patients who received ART between 24 and 35 months, and to 25.7% (29/113) for patients who received ART for >35 months (P = 0.10, χ2 test) (Table 2). Interestingly, despite comparable time on ART, rates of virological failure were higher among men than women, 44/171 (25.7%) versus 84/496 (16.9%), respectively (P = 0.012, χ2 test) (Table 2). This difference was observed for the 3 different categories of time on ART.
HIV Drug Resistance
For survey purposes, successful viral suppression is defined as an HIV RNA level <1000 copies/mL8; therefore, genotypic drug resistance tests were only done for 97 of the 129 patients with viral load >1000 copies/mL. Of the 93 successfully sequenced samples, 78 (83.9%) were resistant to at least 1 drug of their ART regimen and among them 68 (87.2%) harbored resistance mutations to NRTI and NNRTI, 2 (2.6%) were only resistant to NRTI, 7 (8.9%) to NNRTI only, and 1 (1.3%) to NRTI + NNRTI + PI (Table 1). Overall, 73 (93.6%) harbored a mutation at position M184I/V associated with 3TC/FTC resistance and 28 (35.9%) were resistant to AZT and/or d4T because they either accumulated TAMs (n = 17) or harbored a mutation at position V75 (n = 1) or K65R (n = 7) for d4T or the Q151 (n = 2) mutation associated with multi-NRTI resistance. The accumulation of TAMs for some patients resulted also in cross-resistance to Abacavir (n = 3) or didanosine (n = 4), to which patients have never been exposed. Importantly, presence of the K65R mutation compromises also the use of tenofovir (TDF) in second-line regimens.
Among the 76 (97.4%) patients resistant to NNRTIs, the most frequent mutations were at positions K103 (n = 40) and Y181 (n = 38), but major NNRTI mutations were also seen at other positions in decreasing order of importance G190 (n = 15), Y188 (n = 7), K101 (n = 4), V106 (n = 3), M230 (n = 2), and L100 (n = 1). Importantly, 15 patients accumulated also a mutation at position H221, which due to the simultaneous presence of the Y181C mutation predicted also resistance to etravirine (ETV), the new NNRTI drug, for 14 patients and 1 patient harbored the Y181V mutation, also associated with ETV resistance. In addition, 10 patients were predicted with intermediate resistance to ETV due to accumulation of several minor mutations.
Overall, the proportion of ARV-resistant patients increased significantly over time, 8.4% (27/321) for patients under ART for 12-23 months, 12.0% (28/233) for 24-35 months, and 18.6% (21/113) for >35 months on ART (P = 0.013, χ2 test) (Table 2). Although not significant, there was a trend with the number of mutations increasing over time; among the patients receiving ART between 12 and 23 months, 29% (7/24) of those who are resistant to 3TC were also resistant to other NRTI drug versus 54.5% (12/22) and 42% (8/19) when 24-35 or >35 months under ART, respectively (P = 0.22, χ2 test). Similarly, the number of NNRTI mutations increased over time, with 11.1% (3/27), 28.5% (8/28), and 20.0% (4/20) already resistant to ETV after 12-23, 24-35, and >35 months under ART, respectively (P = 0.27, Fisher exact test), and 7.4% (2/27) to 3.5% (1/28) and 20.0% (4/20) with intermediate ETV resistance over time (P = 0.16, Fisher exact test). Similarly as observed for viral load, rates of drug resistance were significantly higher among men than women, 34/171 (19.9%) versus 44/496 (8.8%), respectively (P = 0.0001, χ2 test) (Table 2). Similarly as for viral load, this difference was observed for the 3 different categories of time on ART.
Drug Resistance Mutations in Antiretroviral Therapy-Naive Patients
A total of 283 patients, who declared to be ART naive, were also enrolled in this study during the same period and at the same study sites. Sequences were obtained for 253 (89.4%) samples and were analyzed for the presence of drug resistance mutations with the list developed by an international expert panel under the leadership of the WHO for the surveillance of transmitted drug resistance mutation.11 Drug resistance mutations were identified in 20 (7.9%) strains, and per drug class the values were as follows: 2.4% for PI and 3.2% for NRTI and NNRTI each. In 3 patients, multiple mutations against 2 drug classes were seen (Table 3), suggesting that they were probably not naive. More drug resistance was seen in Kinshasa and Matadi as compared with other cities, 10.9% and 10.1% versus 5.2% and 5.7% for Lubumbashi and Mbuji-Mayi, respectively. In 6 patients only single PI mutations were seen despite the fact that PI are almost not used in the country. In the other samples, the observed mutations correspond to those that can be expected after use of NRTI- and NNRTI-based drug regimens.
Implementation of ART programs is recognized as a public health priority in resource-limited countries, and the wide use of the WHO public health approach allowed a rapid roll out of ART in resource-limited countries.5 However the absence of virological monitoring together with the use of drugs with low genetic barriers could rapidly lead to the emergence of high-level resistance during first-line therapy. Additional factors like deficiencies in health systems, unreliable drug supply systems and storage, and the lack of qualified personnel to prescribe and monitor patients on ART could also create conditions for accelerated development of HIV resistance to ARVs and can differ among countries.6,7 Given these different factors, the few studies, reporting on ART using the public health approach, showed thus contrasted results, with virological success after 12 months ranging from 50% to >90%.22-24
Here we report overall rates of virological failure (>300 copies/mL) and genotypic drug resistance of 19.3% and 11.7%, respectively, in patients who received ART for a median period of 25 months. As expected, virological failure and genotypic drug resistance increased with time on ART from 16.5% and 8.4%, respectively, when 12-23 months on ART to 25.7% and 18.6% when >35 months on ART. Since the first-line regimen included 2 drugs with low genetic barriers, the majority of patients, 70/78 (89.7%) were resistant to at least 2 of the 3 drugs from their treatment. The use of ETV, the next-generation NNRTI, which was initially reported to retain good activity in experienced patients,13 was already compromised for 19.2% (15/78) patients in our study and for an additional 25.6% (20/78) patients, the number of accumulated NNRTI mutations predicted already intermediate resistance. We observed also the K65R mutation in 7/78 (8.9%) patients, compromising the use of TNV in second-line regimens. In our study, the K65R mutation was not restricted to subtype C, but was also observed in 1 subtype A, 1 D, 1 H, 2 URFs involving subtype H and unclassified fragments, and 2 subtype C samples.14,15
The information observed in our study provides useful information for clinicians managing patients and can serve as an indicator of ARV program efficiency in patients still on treatment. Our study does not provide any information on the overall efficiency of the national ART program, because we have not collected information on how many patients died or dropped out of care and how many of them harbor drug resistance mutations. However, it is known that rates of lost to follow-up are the highest in the first year and retention on ART tends to decline thereafter.16 Our estimates of drug resistance in treated patients in DRC are thus most likely minimal estimates. Another limitation of our study is that among the different NGOs and public hospitals that are involved in ART care, we studied only patients who attended the ART care sites developed by the NGO AMO-Congo, which was the main Congolese NGO specialized in HIV/AIDS work. The involvement of AMO-Congo includes voluntary counseling and testing for HIV, medical and psychosocial care, educational support to AIDS orphans, and providing ART and support to treatment adherence, which could explain the relatively low rates of virological failure. Despite the enormous country size, the breakdown of the health system, absence of road infrastructure, and the difficult communications, AMO-Congo was able to implement the standardized national guidelines for ART with almost similar efficiencies in different health centers in different major towns and with relative low virological failures as compared with other sub-Saharan countries.22 Also, the high genetic diversity of the HIV-1 strains and the heterogeneous distribution among the 4 study sites seems to have a low impact on the outcome of the ART program. As observed in previous studies,17-19 many subtypes and CRFs cocirculate, and overall 8 subtypes and 10 different CRFs were identied. Moreover, 3.5% of the strains could not be classified into any of the known subtypes/CRFs and 31.5% of the strains represent complex unique recombinants.
Contradictory reports exist on treatment outcome and gender, but some studies showed that women had a better clinical and virological response to ART and that men were at a higher risk for mortality because they apparently present more advanced disease stages.20,21,25-27 In our study, we have no information on mortality rates but we showed clear gender-related differences in virological outcomes.
Importantly, we also observed that almost 8% of HIV-infected patients who declared being ART naive harbored already drug resistance mutations; however, per drug class, all values are below the 5% threshold defined by WHO.8 Moreover, for 6 patients only single PI mutations were seen, which given to the almost absence of PI use in the country could represent natural polymorphisms related to the high genetic diversity of HIV-1 strains in DRC, especially for mutations M46I or L90M.28 Our results do not reflect recently transmitted drug resistance, but they represent patients who will start ART. The values observed for NRTI and NNRTI resistance mutations observed in DRC are lower than the 10.5% observed in chronically infected patients in 2009 in France but comparable with the 8.7% seen in chronically infected patients in Europe between 1996 and 2002.29,30 As for all studies on drug resistance in ART-naive patients, it cannot be excluded that patients have inadequately declared their lack of exposure to therapy, which could be the case for the 2 patients from Kinshasa with multiple NRTI and NNRTI mutations, resulting in an overestimation of baseline resistance. However, because we did not study recently infected patients, it is also likely that we underestimate the transmission of drug-resistant strains, because of the lower exposure to drug-resistant strains before ART scaling up.30
Overall, our results show clearly that the emergence of HIV drug resistance is of increasing concern, especially after long-term ARV use, in countries where ART is now widely used and can compromise the long-term success in treatment outcomes. As a consequence, the guidelines of the WHO public health approach have been revised in 2010 and recommended less toxic drugs in first-line therapy by replacing d4T by TDF and a more strategic monitoring for ART efficacy.31 Although this latter is still not feasible for the majority of patients on ART in sub-Saharan Africa due to the absence of adequate laboratory facilities and insufficient financial means. Therefore, the system that WHO has established for the surveillance of transmitted drug resistance and the monitoring of ART resistance at sentinel sites should be implemented in all countries to inform health authorities on the efficiency of first- and second-line ART and allow recommendations on future ART strategies.8 The accumulation of drug resistance mutations with time on ART and the significant higher virological failures in DRC among men on ART needs further attention.
The authors would like to express their gratitude to the National AIDS/STD Programme for permission to perform this survey. The authors also wish to thank the directors and staff of the clinics and laboratories in the different regions for providing logistic and technical support in the field and for their cooperation and Sabrina Eymard-Duvernay for statistical analysis.
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