PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
AIDS Rev. Author manuscript; available in PMC 2013 September 16.
Published in final edited form as:
PMCID: PMC3774601
NIHMSID: NIHMS505589

Effects of Political Conflict Induced Treatment Interruptions on HIV Drug Resistance

Abstract

34 million people worldwide were living with the Human Immunodeficiency Virus (HIV) by the end of 2010. Despite significant advances in antiretroviral therapy (ART), drug resistance remains a major deterrent to successful, enduring treatment. Unplanned interruptions in ART have negative effects on HIV treatment outcomes including increased morbidity and mortality, as well as development of drug resistance. Treatment interruptions due to political conflicts, not infrequent in resource-limited settings, result in disruptions in health care, infrastructure, or treatment facilities and patient displacement. Such circumstances are ideal bases for ART resistance development, however there is limited awareness of and data available on the association between political conflicts and the development of HIV drug resistance. In this review we identify and discuss this association and review how varying ART half-lives, genetic barriers, different HIV subtypes, and archived resistance can lead to lack of medication effectiveness upon post-conflict resumption of care. Optimized ART stopping strategies as well as infrastructural concerns and stable HIV treatment systems to ensure continuity of care and rapid resumption of care must be addressed in order to mitigate risks of HIV drug resistance development during and after political conflicts. Increased awareness of such associations by clinicians as well as politicians and stakeholders is essential.

Keywords: Treatment Interruption, Unplanned, Resistance, Political Crises, NNRTI Tail

Introduction

HIV affects 34 million people worldwide of whom over 68% live in Sub-Saharan Africa[1]. Advances in treatment for HIV, specifically the implementation of highly active antiretroviral therapy (HAART), have significantly decreased HIV-associated morbidity and mortality[2]. Evolution of ART resistance remains a major concern in the management of HIV-infected patients around the world, resulting in treatment failure and limited subsequent therapy options[3].

HIV care in developing countries is intertwined with and negatively affected by infrastructural concerns such as lack of electricity, food insecurity, limited housing availability, and unsafe drinking water[4]. Situations leading to these concerns can be related to uncontrollable conditions including nature-based weather disasters, fires, or earthquakes; but also to modifiable, human-caused situations such as wars and political conflicts. Many such conflicts have occurred in the developing world, including over 300 with at least 100 casualties just between 1995 and 2009[5]. Some examples of major conflicts include the Ugandan war in the 1980’s[6], the El Salvadorian civil war in 1980–92[7], the Rwandan refugee crisis in the mid-1990s[8], and the Kenyan post-election crisis in 2007–8[9]. Reports of the consequences of these conflicts on the people they affect have focused primarily on loss of life due to violence, loss of property, and the political ramifications[10]. Comprehensive understanding of the specific implications on health in general and HIV-infected individuals in particular is lacking.

Negative outcomes of political conflicts may have significant effects on HIV patient care. In addition to mental health outcomes that may disrupt pill-taking routines, HIV-infected patients may experience interruption of ART due to loss of or inability to adequately store medications, inability to attend clinics and pharmacy stock-outs[1113]. A resulting treatment interruption, whether planned[14,15] or unplanned, is a significant problem in HIV therapy and is not recommended[16].

In this review we make the linkage between unplanned ART interruptions induced by political conflicts and their effect on HIV-infected patients. We discuss conflicts and their effects on treatment interruption; why interruptions are not favorable in HIV care and how they can result in development of ART resistance; the mechanisms of resistance pathways during and after treatment interruption; and recommendations to prevent them. Ultimately, the combined effects of consistently available HIV treatment systems, infrastructure stabilization and optimized ART cessation strategies (if needed), together with increased political insight, will minimize the harmful effects of political conflicts on HIV patient care. Though uncontrollable by patients, such conflicts are programmatically modifiable.

Political Conflicts, Treatment Interruption, and Health Care Impact

Conflicts Occur in Resource Limited Settings

Political conflicts occur all too frequently in resource limited settings, unfortunately producing almost unavoidable turmoil resulting in violence and negative health consequences[10]. Conflicts often have a basis in economics and inequality, destabilizing communities by slowing economic development and increasing insecurity, and therefore have a profound effect in the developing world[17]. These factors tend to be weak in developing countries even during unconflicted times, and conflict thus has an exacerbating effect[17]. In developing countries conflicts tend to include such tactics as disruption of agricultural production, systematic destruction of service infrastructure, sabotage of water and electrical supplies, poisoning of wells, killing of livestock, burning of harvests, elimination of markets, and confiscation of property, tactics which are less often used in developed world conflicts[17]. All of these aspects combine to create a destructive cycle of poverty, conflict, under-development, and lack of economic growth.

There are many examples of political conflicts in the developing world, some more studied than others [69,13,18,19]. Such conflicts led to fatalities, displacement of health professionals and the affected populations; discontinuation of health services and treatments; decrease in the health budgets, life expectancy and immunization rates; disease outbreaks from a lack of sanitary food and water sources; significant increases in childhood malnutrition, morbidity, and morality; and shortages in basic supplies and medications.

Conflicts can Lead to Treatment Interruptions

Episodes of political insecurity in developing countries can quickly destabilize ART programs and lead to treatment interruptions[20]. Conflicts can limit drug availability due to supply chain interruptions and personnel displacement[21]. At any time lack of available and affordable transport can be a major deterrent to access to care[22]. Thus during times of conflict, exacerbated lack of infrastructure and unsafe travel environments can further deter patient visits to medical clinics, limiting access to prescribed drugs. Treatment may also be interrupted due to displacement of patients owing to destruction of homes, violent environments, or lack of necessities[13]. Furthermore, some patients may experience depression or hopelessness following a conflict and its consequences, de-motivating them from seeking or continuing care[13]. Data on HIV treatment interruption following political crises are limited. In Nairobi, Kenya, researchers found that treatment interruption was 71% higher during the 2007–8 political conflict compared to unconflicted times[12]. We suspect these odds were even higher in Eldoret and surrounding Kenyan rural areas, where the violence was more severe. Despite a lack of HIV-specific data, the detrimental health consequences of conflicts, particularly in the developing world, have been established.

Treatment Interruption and HIV Drug Resistance

Treatment Interruptions are not Favorable in HIV Infection

Treatment interruptions decrease the success of HIV therapy, resulting in increased mortality and morbidities such as opportunistic infections [14,15]. The effects of structured, or planned, treatment interruptions have been prospectively and retrospectively studied as potentially beneficial treatment strategies, mainly by (i) a timed-cycle strategy in which ART is stopped for a fixed time period; or (ii) a CD4-guided strategy in which treatment is stopped at a predetermined high CD4 count and restarted at a predetermined low CD4 count [14,15]. A systematic review of structured interruptions demonstrated lack of benefit in people with unsuppressed HIV infection and evidence of possible harm in suppressed patients [14,15].

Table 1 demonstrates major studies of the effects of structured ART interruptions on the immune system (CD4-cell counts), HIV viral load, and treatment outcome. The majority of studies show negative effects on treatment outcome. Though some conflicting data exist, plausible explanations for this discordance include usage of CD4 count as outcome, which may not be directly applicable to treatment outcome in interruption circumstances[23,24]; cessation of treatment arms before study endpoint due to large numbers of failures, which may have left only more moderate groups for analysis and conclusions[2326]; and minimal follow-up times, which may not have captured the majority of failures[27].

Table 1
*: Major Studies of Structured HIV Treatment Interruption

Unstructured treatment interruptions (Table 2) consistently have unfavorable outcomes and should be avoided whenever possible, though studies thus far have focused on interruption during the normal course of treatment as opposed to during conflicts. In such times, more detrimental outcomes are expected, concerning abruptness, length, totality and associated circumstances and stress. Notably, no major cohort studies on unstructured ART interruption have been completed in the developing world.

Table 2
††: Major Studies‡‡ of Unstructured HIV Treatment Interruption

Treatment interruptions are currently not recommended in HIV patient management [28,29]. Some studies have stated that interruptions can be considered favorable to a treatment plan by relieving negative side effects of medications, alleviating some cost of treatment, or allowing resistant virus to revert to wild type form [25,30]. However, any advantages do not outweigh the risks of resistance development, limitation in subsequent regimens and disease progression, and therefore treatment interruption is not part of recommended HIV-care [31].

Treatment Interruptions Lead to HIV Drug Resistance

HIV is characterized by error prone reverse transcription and high production and turnover rates[32]. The combination of these mechanisms in the presence of recombination leads to numerous mutations that are generated during the viral life cycle, resulting in a large and diverse viral population of quasispecies[33]. Though as little as a single amino acid substitution can produce high levels of drug resistance[34], HAART reduces the probability of resistance evolution by incorporating several drug classes that are detrimental to HIV via different mechanistic actions, thus ensuring treatment success.

Interruptions in HIV treatment can have varying harmful effects on development of drug resistance with serious implications for future treatment[35]. Upon inadequate ART exposure, such as may occur with non-adherence or during a conflict-related unplanned treatment interruption, viral variants with mutations that confer drug-specific selective advantage may become more prevalent[36]. In such a scenario, upon resumption of care and reinstitution of ART, the now-predominant viral population will be resistant to the HAART regimen and treatment failure will follow[36]. Non-nucleoside reverse transcriptase inhibitor containing regimens, the vast majority of first-line HAART in resource limited settings, are often the drug class most susceptible to the development of drug resistance[37]. Such regimens, which are usually continued upon post-interruption resumption of care, may no longer be effective if resistance has developed, resulting in a higher risk of morbidities and mortality [16]. Although it is necessary to change regimens to second- or third-line regimens for patients who have developed such resistance, such options and the monitoring capacity to make such decisions, are often restricted in resource limited settings.

A window into the potential effects of treatment interruption on the development of drug resistance can be derived from a specific case – the use of single dose nevirapine to prevent mother to child HIV transmission. This mode of therapy, given to mother and baby before and after birth, respectively, has been used in resource limited settings since the HIVNET 012 study demonstrated in 2003 a 41% reduction in HIV vertical transmission [38]. Though the World Health Organization removed single dose nevirapine from their guidelines for prevention of mother-to-child transmission in resource limited settings in 2010, this preventative treatment continues to be used in some developing countries[3]. During the few days after ingestion of single dose nevirapine, HIV is exposed to decreasing blood levels of this medication, during which drug resistance develops, as can occur after treatment interruption. Further mechanistic details are provided below. As a result, the use of single dose nevirapine can produce resistance to nevirapine in as many as 25–75% of women treated with it[39]. The implications of nevirapine resistance can be daunting as it limits use of subsequent non-nucleoside reverse transcriptase inhibitor containing HAART regimens, which are the mainstay of first-line ART in the developing world[40].

Mechanisms of Drug Resistance Following Treatment Interruptions

Various biologic mechanisms may be related to the process of drug resistance development following treatment interruptions. As outlined below, some of them are more understood than others and their integration and occurrence in resource limited settings may be detrimental.

Antiretroviral Drug Levels and Half Lives

Varying half-lives of ARTs significantly affect patient drug levels when therapy is interrupted[41]. When drugs given simultaneously as part of HAART have significantly different plasma half-lives, their metabolism and clearance times differ[42]. As a result, during simultaneous cessation of all drugs, as occurs in unplanned treatment interruptions, drugs with longer half-lives remain detectable for a prolonged period of time, resulting in a functional mono- or dual-therapy[43]. Such circumstances, which are somewhat similar to the single dose nevirapine circumstances discussed above, significantly increase the likelihood of drug resistance development and jeopardize current and subsequent ART. The two main factors that influence the development of resistance in this scenario are[43]: (1) time that a single drug remains detectable at a concentration sufficient for viral replication; and (2) genetic barrier of the drug.

Time of Drug Detectability

The World Health Organization-recommended first-line ART in resource limited settings includes two nucleoside/nucleotide reverse transcriptase inhibitors (tenofovir or zidovudine and lamivudine or emtricitabine), and one non-nucleoside reverse transcriptase inhibitor (efavirenz or nevirapine)[3]. In second line recommended ART protease inhibitors (atazanavir/ritonavir or lopinavir/ritonavir) replace the non-nucleoside reverse transcriptase inhibitor[3].

The plasma half-lives of these drugs, listed in Table 3, demonstrate clear differences[43]. Pharmacokinetically, after one half-life 50% of the drug is eliminated from the body and only 50% remains. Similarly, after two half-lives, 75% remains and after five half-lives just over 3% remains, and as a rule of thumb it has been virtually eliminated from the body[44]. As seen in Table 3, non-nucleoside reverse transcriptase inhibitors have lengthy half-lives therefore remain in the body days to weeks longer than nucleoside reverse transcriptase inhibitors upon abrupt treatment cessation. This functional mono-therapy (or ‘tail’) exposes the virus to decreasing drug levels, increasing the likelihood of resistance evolution. The longer the ‘non-nucleoside reverse transcriptase inhibitor tail’, the more significant are the potential effects of the treatment interruption [30], similarly to the effect after single dose nevirapine. Though less studied, differing protease inhibitor and nucleoside reverse transcriptase inhibitor half-lives can potentially have similar consequences.

Table 3
†††: Plasma Half-Lives of WHO-recommended First and Second-Line Antiretroviral Therapy

Drug Genetic Barrier

The genetic barrier of a drug refers to the number of mutations that need to occur in the viral RNA in order to render a drug ineffective, while maintaining viral fitness[45]. Non-nucleoside reverse transcriptase inhibitors such as efavirenz and nevirapine have particularly low genetic barriers, and even one mutation is enough to cause high-level resistance[46]. For example, a single amino acid mutation of lysine (K) to asparagine (N) at the HIV reverse transcriptase position 103 (K103N) leads to high level resistance to both nevirapine and efavirenz[46]. Other ARTs, such as most nucleoside reverse transcriptase inhibitors that are part of first-line regimens, and protease inhibitors that are part of second-line regimens, have higher genetic barriers to resistance. Upon treatment interruption differences in half-lives and genetic barriers of medications of one HAART regimen can result in drug resistance evolution. This most likely will initially be to non-nucleoside reverse transcriptase inhibitors for reasons discussed above, however, due to lack of close virologic monitoring in resource limited settings[47], resistance can subsequently develop to other drugs that are part of the regimen.

The Subtype Variable

Nine group M subtypes, several sub-subtypes, and numerous recombinant forms are responsible for the vast majority of HIV-1 global infections[48]. Subtype B is the most prevalent in the developed world while non-subtype B variants predominate globally [48,49]. The majority of research and development of ART has been in industrialized countries, and therefore knowledge of drug resistance pathways in subtype B is most complete, while data are still being collected for non-B subtypes. Despite significant similarities, there is growing evidence on inter-subtype differences in drug resistance development [50]. This is reasonable as different subtypes and recombinant forms are genetically and phylogenetically distinct throughout their genome, including the pol gene from which the majority of the data are derived [51,52]. Differences in the development of drug resistance after exposure to single dose nevirapine have been reported among HIV-1 subtypes, involving increased susceptibility of individuals infected with subtype C to nevirapine resistance compared to those infected with subtypes B or D[53]. Subtype specific effects on the evolution of drug resistance following treatment interruptions are not known, but the analogy to single dose nevirapine as well as the abundance of viral diversity worldwide is concerning and mandates close follow-up[52].

Archived Resistance

Current ART can suppress but not eradicate HIV[54]. A primary cause for this unfortunate circumstance is the incorporation of replication-competent pro-viral HIV DNA into human DNA in cells such as peripheral blood mononuclear cells. The viral DNA remains dormant at sub-detectable levels even during effective ART[55]. If that archived virus was previously exposed to low drug levels, as occurs immediately following a treatment interruption, it may contain drug resistance mutations. Consequently, that drug resistant variant may be permanently incorporated into human DNA, and re-emerge at later times[56]. In this context, restarting the same HAART regimen upon post conflict resumption of care, as is usually the case in resource limited settings, can provide selective advantage to that viral variant, which can then reemerge and lead to treatment failure.

Guidelines for Stopping ART

Several global and United States based agencies publish guidelines on HIV treatment, prevention, and care, including the World Health Organization[3], the USA Department of Health and Human Services[28] and the International AIDS Society-USA[29]. The recommendations regarding treatment interruptions as incorporated in these and other guidelines are given in Table 4. The World Health Organization as well as the international organization Doctors Without Borders[57] guidelines currently do not contain any recommendations regarding the interruption of ART. The thorough Department of Health and Human Services guidelines recommend against planned interruptions but provide conditional guidelines for short-term interruption (<2–3 days) in regimens with similar half-lives, in line with the above discussion. International AIDS Society-USA has issued brief guidelines for ART stopping procedures, but overall recommend against any treatment interruption. Organizations in Europe such as the British HIV Association[58] and European AIDS Clinical Society[59] have issued similar blanket recommendations against interruption. Finally, the Canadian HIV Trial Network (most recently issued 13 years ago) gives vague recommendations instructing physicians to counsel patients on any interruption[60].

Table 4
‡‡‡: Guidelines for Treatment Interruption of ART

Taken together, treatment interruptions are generally not recommended by guidelines that address them, due to both known and unknown risks and to unclear optimal stopping strategies. Such data are essential and must be provided to policy makers and guideline writing committees. No recommendations have as yet approached the subject of interruption in the context of political conflicts.

Conclusions and Path Forward

Political conflicts occur far too frequently in developing countries and their long-term implications are not always considered a top priority. Regardless of the cause, the association between conflict and health-care consequences in general and HIV in particular, is understudied and is not often considered in real-time decisions during conflicts. The linkage between conflicts and their potential consequences for the HIV pandemic is critical to understand and apply. This review emphasizes this linkage, its circumstances and the importance of understanding potential complications and their implications.

Political conflicts destabilize health care systems, which can lead to disruptions in access to HIV care and interruptions of ART. Whether due to limited drug availability, lack of infrastructure, unsafe travel conditions, or displacement due to violence or home destruction, the potential results include evolution of drug resistance, increased morbidity, and eventually mortality. Factors discussed in this review, such as ART half-lives, genetic barriers, viral diversity, and archived resistance, can lead to harmful outcomes upon resumption of care after conflict-induced interruption.

Despite confirmed negative effects of treatment interruptions, in circumstances of political conflicts they are often unavoidable. Research is therefore needed to determine optimal ART stopping and restarting strategies for patients who find themselves in situations of unplanned interruptions. Such strategies should take into account the regimen prior to interruption, medication half-life, replacement therapy options, close monitoring, and perhaps, if feasible, resistance testing upon resumption of care prior to re-starting therapy and close monitoring thereafter. An additional strategy should encompass implementation of contingency treatment plans in developing countries addressing factors like consistent drug supplies, improved patient follow-up, and education for health care providers, implementation of viral load monitoring and resistance testing, and availability of multiple treatment regimens. In particular, relief agencies would benefit from an increased focus on identifying HIV positive victims for intensive follow up during times of crisis. Patient concerns for transport and access to clinics including road conditions and transport safety, as well as water and food safety and availability, must also be addressed. Implementing cohort studies on unstructured ART interruption in the developing world is important.

In addition to research, education and patient and provider awareness and preparedness, policy makers and politicians throughout the world can directly impact the lives of HIV-infected patients by avoiding conflicts and their consequences. Perhaps increased awareness of this long-term and often overlooked consequence will provide opportunity for re-consideration in similar future circumstances. Given the severity of the potential effects discussed here, it would be advantageous for political leaders to begin a preemptive discourse on prevention of violence, and for treatment programs a contingency planning for HIV patients before an imminent conflict.

Acknowledgments

Marita Mann was supported by the Brown University Framework in Global Health Program, National Institutes of Health grant R25-TW008102. Rami Kantor is supported by National Institutes of Health grants RO1-AI66922 and P30AI042853. The authors thank Mr. Jonathan Snow from the Department of Politics at Brandeis University for assistance with literature on political conflicts.

References

1. UNAIDS. Report on the Global AIDS Epidemic. 2010.
2. Eron JJ. Managing antiretroviral therapy: changing regimens, resistance testing, and the risks from structured treatment interruptions. J Infect Dis. 2008;197 (Suppl 3):S261–71. [PubMed]
3. WHO. Recommendations for a Public Health Approach. 2010. Antiretroviral Therapy for HIV Infection in Adults and Adolescents 2010 Revision. [PubMed]
4. Dionisio D, Esperti F, Messeri D, Vivarelli A. Priority strategies for sustainable fight against HIV/AIDS in low-income countries. Curr HIV Res. 2004;2:377–93. [PubMed]
5. Political Instability Task Force Worldwide Atrocities Dataset. Accessed at http://eventdata.psu.edu/data.dir/atrocities.html.
6. Dodge CP. Health implications of war in Uganda and Sudan. Soc Sci Med. 1990;31:691–8. [PubMed]
7. Ugalde A, Selva-Sutter E, Castillo C, Paz C, Canas S. Conflict and health: The health costs of war: can they be measured? Lessons from El Salvador. BMJ. 2000;321:169–72. [PMC free article] [PubMed]
8. Goma Epidemiology Group. Public health impact of Rwandan refugee crisis: what happened in Goma, Zaire, in July, 1994. Lancet. 1995;345:339–44. [PubMed]
9. Feikin DR, Adazu K, Obor D, et al. Mortality and health among internally displaced persons in western Kenya following post-election violence, 2008: novel use of demographic surveillance. Bull World Health Organ. 2010;88:601–8. [PubMed]
10. Feldbaum H, Lee K, Michaud J. Global health and foreign policy. Epidemiol Rev. 2010;32:82–92. [PMC free article] [PubMed]
11. Kranzer K, Lewis JJ, Ford N, et al. Treatment interruption in a primary care antiretroviral therapy program in South Africa: cohort analysis of trends and risk factors. J Acquir Immune Defic Syndr. 2010;55:e17–23. [PMC free article] [PubMed]
12. Pyne-Mercier LD, John-Stewart GC, Richardson BA, et al. The consequences of post-election violence on antiretroviral HIV therapy in Kenya. AIDS Care. 2011;23:562–8. [PMC free article] [PubMed]
13. Vreeman R, Nyandiko W, Sang E, Musick B, Braitstein P, Wiehe S. Impact of the Kenya post-election crisis on clinic attendance and medication adherence for HIV-infected children in western Kenya. Confl Health. 2009;3:5. [PMC free article] [PubMed]
14. Pai NP, Lawrence J, Reingold AL, Tulsky JP. Structured treatment interruptions (STI) in chronic unsuppressed HIV infection in adults. Cochrane Database Syst Rev. 2006;3:CD006148. [PubMed]
15. Pai NP, Tulsky JP, Lawrence J, Colford JM, Jr, Reingold AL. Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults. Cochrane Database Syst Rev. 2005:CD005482. [PubMed]
16. Kranzer K, Ford N. Unstructured treatment interruption of antiretroviral therapy in clinical practice: a systematic review. Trop Med Int Health. 2011 [PubMed]
17. Pedersen D. Political violence, ethnic conflict, and contemporary wars: broad implications for health and social well-being. Soc Sci Med. 2002;55:175–90. [PubMed]
18. Arnold G. Cassell. 1995. Wars in the Third World since 1945.
19. [Accessed July 07, 2011];A Country Study: El Salvador. at http://lcweb2.loc.gov/frd/cs/svtoc.html.
20. Veenstra N, Whiteside A, Lalloo D, Gibbs A. Unplanned antiretroviral treatment interruptions in southern Africa: how should we be managing these? Global Health. 2010;6:4. [PMC free article] [PubMed]
21. Reid T, van Engelgem I, Telfer B, Manzi M. Providing HIV care in the aftermath of Kenya’s post-election violence Medecins Sans Frontieres’ lessons learned January - March 2008. Confl Health. 2008;2:15. [PMC free article] [PubMed]
22. Geng EH, Bangsberg DR, Musinguzi N, et al. Understanding reasons for and outcomes of patients lost to follow-up in antiretroviral therapy programs in Africa through a sampling-based approach. J Acquir Immune Defic Syndr. 2010;53:405–11. [PMC free article] [PubMed]
23. Cardiello PG, Hassink E, Ananworanich J, et al. A prospective, randomized trial of structured treatment interruption for patients with chronic HIV type 1 infection. Clin Infect Dis. 2005;40:594–600. [PubMed]
24. Ananworanich J, Siangphoe U, Hill A, et al. Highly active antiretroviral therapy (HAART) retreatment in patients on CD4-guided therapy achieved similar virologic suppression compared with patients on continuous HAART: the HIV Netherlands Australia Thailand Research Collaboration 001. 4 study. J Acquir Immune Defic Syndr. 2005;39:523–9. [PubMed]
25. Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet. 2006;368:459–65. [PubMed]
26. Reynolds SJ, Kityo C, Hallahan CW, et al. A randomized, controlled, trial of short cycle intermittent compared to continuous antiretroviral therapy for the treatment of HIV infection in Uganda. PLoS One. 2010;5:e10307. [PMC free article] [PubMed]
27. Walmsley SL, Thorne A, Loutfy MR, et al. A prospective randomized controlled trial of structured treatment interruption in HIV-infected patients failing highly active antiretroviral therapy (Canadian HIV Trials Network Study 164) J Acquir Immune Defic Syndr. 2007;45:418–25. [PubMed]
28. DHHS. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services; 2011. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
29. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010;304:321–33. [PubMed]
30. Trignetti M, Sing T, Svicher V, et al. Dynamics of NRTI resistance mutations during therapy interruption. AIDS Res Hum Retroviruses. 2009;25:57–64. [PubMed]
31. Danel C, Moh R, Chaix ML, et al. Two-months-off, four-months-on antiretroviral regimen increases the risk of resistance, compared with continuous therapy: a randomized trial involving West African adults. J Infect Dis. 2009;199:66–76. [PubMed]
32. Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse transcriptase from HIV-1. Science. 1988;242:1171–3. [PubMed]
33. Lauring AS, Andino R. Quasispecies theory and the behavior of RNA viruses. PLoS Pathog. 2010;6:e1001005. [PMC free article] [PubMed]
34. Shuck-Lee D, Chang H, Sloan EA, Hammarskjold ML, Rekosh D. Single-nucleotide changes in the HIV Rev-response element mediate resistance to compounds that inhibit Rev function. J Virol. 2011;85:3940–9. [PMC free article] [PubMed]
35. Bangsberg DR, Kroetz DL, Deeks SG. Adherence-resistance relationships to combination HIV antiretroviral therapy. Curr HIV/AIDS Rep. 2007;4:65–72. [PubMed]
36. Martinez-Picado J, Wai Yan Tam L. Risk of selecting resistance mutations during treatment interruption. Curr Opin HIV AIDS. 2007;2:6–13. [PubMed]
37. Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR. Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS. 2009;23:1035–46. [PMC free article] [PubMed]
38. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet. 2003;362:859–68. [PubMed]
39. Lockman S. Prevention of mother-to-child transmission, drug resistance, and implications for response to therapy. Curr Opin HIV AIDS. 2008;3:166–72. [PubMed]
40. Lockman S, Hughes MD, McIntyre J, et al. Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med. 2010;363:1499–509. [PMC free article] [PubMed]
41. Chisholm-Burns Marie KJ, Chisholm-Burns Marie A, Patrick Malone, Schwinghammer Terry L, Wells Barbara G, Malone Patrick M, Kolesar Jill M. Professional MH, editor. Pharmacotherapy Principles and Practice. 2. 2010.
42. Bazzoli C, Jullien V, Le Tiec C, Rey E, Mentre F, Taburet AM. Intracellular Pharmacokinetics of Antiretroviral Drugs in HIV-Infected Patients, and their Correlation with Drug Action. Clin Pharmacokinet. 2010;49:17–45. [PubMed]
43. Taylor S, Boffito M, Khoo S, Smit E, Back D. Stopping antiretroviral therapy. AIDS. 2007;21:1673–82. [PubMed]
44. Hansen KNGP. In: Text Book Of Clinical Pharmacy. Hansen KNMCN, Parthasarathi G, editors. Orient Blackswan; 2004.
45. Brian WJ, Mahy MHVR. Desk Encycolopedia of General Virology. Academic Press; 2009.
46. Ghosn J, Chaix ML, Delaugerre C. HIV-1 resistance to first- and second-generation non-nucleoside reverse transcriptase inhibitors. AIDS Rev. 2009;11:165–73. [PubMed]
47. Gupta RK, Hill A, Sawyer AW, et al. Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9:409–17. [PubMed]
48. Hemelaar J, Gouws E, Ghys PD, Osmanov S. Global trends in molecular epidemiology of HIV-1 during 2000–2007. AIDS. 2011;25:679–89. [PMC free article] [PubMed]
49. Kantor R, Katzenstein D. Drug resistance in non-subtype B HIV-1. J Clin Virol. 2004;29:152–9. [PubMed]
50. Kantor R, Katzenstein DA, Efron B, et al. Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration. PLoS Med. 2005;2:e112. [PMC free article] [PubMed]
51. Kantor R. Impact of HIV-1 pol diversity on drug resistance and its clinical implications. Curr Opin Infect Dis. 2006;19:594–606. [PubMed]
52. Kantor R, Katzenstein D. Polymorphism in HIV-1 non-subtype B protease and reverse transcriptase and its potential impact on drug susceptibility and drug resistance evolution. AIDS Rev. 2003;5:25–35. [PubMed]
53. Eshleman SH, Guay LA, Wang J, et al. Distinct patterns of emergence and fading of K103N and Y181C in women with subtype A vs. D after single-dose nevirapine: HIVNET 012. J Acquir Immune Defic Syndr. 2005;40:24–9. [PubMed]
54. Lafeuillade A, Stevenson M. The search for a cure for persistent HIV reservoirs. AIDS Rev. 2011;13:63–6. [PubMed]
55. Turriziani O, Andreoni M, Antonelli G. Resistant viral variants in cellular reservoirs of human immunodeficiency virus infection. Clin Microbiol Infect. 2010;16:1518–24. [PubMed]
56. Noe A, Plum J, Verhofstede C. The latent HIV-1 reservoir in patients undergoing HAART: an archive of pre-HAART drug resistance. J Antimicrob Chemother. 2005;55:410–2. [PubMed]
57. Médecins Sans Frontières. Clinical HIV/AIDS Care Guidelines for Resource-poor Settings. Apr, 2006.
58. Gazzard BG, Anderson J, Babiker A, et al. British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med. 2008;9:563–608. [PubMed]
59. European AIDS Clinical Society. European Guidelines for treatment of HIV infected adults in Europe. 2011. Oct,
60. Rachlis AR, Zarowny DP. Guidelines for antiretroviral therapy for HIV infection. Canadian HIV Trials Network Antiretroviral Working Group. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 1998;158:496–505. [PMC free article] [PubMed]
61. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–96. [PubMed]
62. Maggiolo F, Airoldi M, Callegaro A, et al. CD4 cell-guided scheduled treatment interruptions in HIV-infected patients with sustained immunologic response to HAART. AIDS. 2009;23:799–807. [PubMed]
63. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet. 2006;367:1981–9. [PubMed]
64. Pogany K, van Valkengoed IG, Prins JM, et al. Effects of active treatment discontinuation in patients with a CD4+ T-cell nadir greater than 350 cells/mm3: 48-week Treatment Interruption in Early Starters Netherlands Study (TRIESTAN) J Acquir Immune Defic Syndr. 2007;44:395–400. [PubMed]
65. Ruiz L, Paredes R, Gomez G, et al. Antiretroviral therapy interruption guided by CD4 cell counts and plasma HIV-1 RNA levels in chronically HIV-1-infected patients. AIDS. 2007;21:169–78. [PubMed]
66. Leon A, Martinez E, Milinkovic A, et al. Influence of repeated cycles of structured therapy interruption on the rate of recovery of CD4+ T cells after highly active antiretroviral therapy resumption. J Antimicrob Chemother. 2009;63:184–8. [PubMed]
67. DART Trial Team. Fixed duration interruptions are inferior to continuous treatment in African adults starting therapy with CD4 cell counts < 200 cells/microl. AIDS. 2008;22:237–47. [PubMed]
68. Maggiolo F, Ripamonti D, Gregis G, Quinzan G, Callegaro A, Suter F. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. AIDS. 2004;18:439–46. [PubMed]
69. Holkmann Olsen C, Mocroft A, Kirk O, et al. Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death. HIV Med. 2007;8:96–104. [PubMed]
70. d’arminio Monforte A, Cozzi-Lepri A, Phillips A, et al. Interruption of highly active antiretroviral therapy in HIV clinical practice: results from the Italian Cohort of Antiretroviral-Naive Patients. J Acquir Immune Defic Syndr. 2005;38:407–16. [PubMed]
71. Kaufmann GR, Elzi L, Weber R, et al. Interruptions of cART limits CD4 T-cell recovery and increases the risk for opportunistic complications and death. AIDS. 2011;25:441–51. [PubMed]
72. Knobel H, Urbina O, Gonzalez A, et al. Impact of different patterns of nonadherence on the outcome of highly active antiretroviral therapy in patients with long-term follow-up. HIV Med. 2009;10:364–9. [PubMed]
73. Wolf E, Hoffmann C, Procaccianti M, et al. Long-term consequences of treatment interruptions in chronically HIV-1-infected patients. Eur J Med Res. 2005;10:56–62. [PubMed]