Antiretroviral Therapy

Newer medications and formulations have addressed many of the limitations of earlier regimens in terms of short and long-term antiretroviral toxicities. Therapies against HIV have become easier to administer, less toxic and more potent. Undoubtedly, concerns about tenofovir- associated kidney dysfunction, bone demineralization and potential increases in cardiovascular disease risk remain [34-37]. Nevertheless, newer protease inhibitors have been associated with far fewer adverse effects, such as dyslipidemia, insulin resistance and gastrointestinal in- tolerance [38,39]. Likewise, newer nucleoside reverse- transcriptase inhibitors have virtually no associated lipodystrophy or major mitochondrial dysfunction [40]. Novel HIV treatments are able now to offer more con- venient dosing. Fixed-dose combination options adminis- tered once daily have led to more uniformity in initial antiretroviral therapy. In assessing prescribing practices in our clinic, the most dramatic shift in drug selection in- volved the incremental use of emtricitabine plus tenofovir plus efavirenz, from 0% in 2003 to 85% in 2007. This reflected better acceptance of a simpler regimen that can be administered as a single, daily pill [41]. These dramatic advances have tremendously impacted clinical practice and compelled clinicians and investigators to revisit the

HIV and diabetes are both chronic diseases that significantly affect life style. When they intersect, the treatment regimens required for both diseases can be overwhelming for patients. Understanding the glucose disturbances that are possible with antiretroviral therapy/HAART, performing appropriate screening for glucose intolerance and diabetes and making prudent changes in the HIV therapy when necessary, and treating patients for alterations in glucose metabolism are the key components of care for at risk patients.

The progression of exhaustion and immune dysfunction in chronic HIV infection can be halted, and even reverted, with the initiation of antiretroviral therapy (ART; ref. 11). To date, several classes of antiretroviral medication with distinct mechanisms have been discovered. Common ART regimens use a combination of 3 antiretroviral agents with 2 modes of actions (12). Nucleoside reverse tran- scriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) block viral RNA transcription by inhibiting reverse transcriptase, protease inhibitors (PIs) block viral enzyme protease and prevent the maturation of the virus, and integrase inhibitors act against the viral DNA integration into the host genome (13). The newest class represents the integrase strand transfer inhibi- tors (INSTIs) — raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DLG). Because INSTIs spe- cifically block the process of viral DNA integration into the host genome by occupying the active site of integrase, their effects are thought to be highly specific (14). Given the superior profile of INSTIs, including reduced potential for drug or food interactions, similar or better tolerability and safety, while showing noninferiority in viral suppression (15–18), INSTI-based regimens have been recommended as initial therapy for many people diagnosed with HIV (19).

To describe the relation between the incidence of myocardial infarction and exposure to combina- tion antiretroviral therapy, each person’s follow-up was divided into a series of consecutive one-month periods. A patient’s cumulative exposure to therapy at the start of each period was calculated (includ- ing the duration of treatment before enrollment in this study and during follow-up), and the result was used to assign the patient-month (and any end- point events that occurred during that month) to the appropriate exposure category. The exposure cat- egories were as follows: no exposure or less than one year, one to two years, two to three years, three to four years, and more than four years of exposure. Follow-up data from patients with more than five years of exposure were limited. The incidence rate in each of these categories was calculated as the num- ber of events occurring divided by the total number of patient-years in that category.

Antiretroviral therapy in the developed world has resulted in substantial reductions in HIV-associated morbidity and mortality, changing an HIV diagnosis from a likely death sentence into a manageable chronic infection (F. J. Palella, Jr., K. M. Delaney, A. C. Moorman, M. O. Loveless, J. Fuhrer, G. A. Satten, D. J. Aschman, and S. D. Holmberg, N. Engl. J. Med. 338:853–860, 1998). Several million years of life have been saved by effective anti-HIV treatment, although these successes should not obscure the magnitude of the ongoing worldwide HIV epidemic (R. P. Walensky, A. D. Paltiel, E. Losina, L. M. Mercincavage, B. R. Schackman, P. E. Sax, M. C. Weinstein, and K. A. Freedberg, J. Infect. Dis. 194:11–19, 2006). Readers of the Journal of Virology are doubtless aware of the fundamental advances in retrovirology that have made possible the development of potent inhibitors of HIV replication. In this review, we focus on the issues surrounding how these drugs and drug regimens are actually used in clinical settings. Their proper use requires detailed knowledge of the natural history of HIV infection, the pharmacology of the individual drugs, the complexities of drug-drug interactions, and the use of sophisticated molecular tests for monitoring of viral load, immuno- logic response, and drug resistance.

Children identified as HIV-1 RNA positive at birth and initiated on ART (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI94582DS1) as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial (25) were studied for evidence of HIV-1 replication during ART. We used single-genome amplification and sequenc- ing (SGS) to compare HIV p6-PR-RT sequences obtained from plasma or PBMCs near the time of ART initiation (baseline) and after 7 to 9 years on ART (long-term ART) in 10 children (Supple- mental Table 1). The fragment analyzed is 1.2 kb in length and covers the p6 region of gag as well as protease and the first 700 bp of reverse transcriptase in the pol gene. The sequences from the 10 children are shown in neighbor-joining (NJ), p-distance trees in Figure 1. Eight had undetectable plasma HIV-1 RNA through- out the period of observation and had initiated treatment by 10 months of age (median: 2.45 months; range: 1.8–9.9 months). Two children, serving as controls, did not have plasma viremia suppres- sion on ART for fifteen to thirty months. To look for evidence of ongoing viral replication during ART, HIV populations in samples taken at baseline were compared with the populations present after long-term ART. Three measures of evolution were assessed for significant change over time: (a) HIV-1 genetic diversity, mea- sured as the average pairwise distance (APD), from early infection to long-term infection; (b) genetic divergence from the founder virus(es) using a test for panmixia (3, 12, 26, 27); and (c) root-to-tip distances in maximum-likelihood (ML) trees (3, 12, 27). ML trees were rooted in 2 ways: first, on an outgroup (HIV subtype C con- sensus; www.hiv.lanl.gov), and second, on the majority sequence of the baseline sample (Table 1).

Abstract: An increasing number of HIV-infected women of childbearing age are initiating antiretroviral therapy (ART) worldwide. This review aims to discuss updated data of the eligible ART regimens and their role in inducing birth defects in utero. Zidovudine and lamivudine plus a non-nucleoside reverse-transcriptase inhibitor or protease inhibitor (PI) is the first-line regimen applied. The role of zidovudine exposition monotherapy or associated with other ART in inducing birth defects remains inconclusive. The main organ systems involved are genitourinary and cardiovascular. For HIV-infected pregnant women, World Health Organization (WHO) guidelines up to 2010 recommend the same group of drugs that are prescribed to nonpregnant women. The exception is efavirenz, which has been associated with an increase in the risk of teratogenicity. Increased rates of birth defects were found in large cohorts and computational studies conducted recently in infants exposed to efavirenz-containing regimens. The combination of zidovudine and lamivudine and lopinavir/ritonavir is one of the most used ART regimens for prevention of mother-to-child-transmission. Conflicting data about the role of PI exposure in utero and birth defects have been reported. However, a reduced number of studies evaluating the role of PI in inducing birth defects in women are available. An association between prematurity and PI exposure in pregnancy was extensively described. Some questions arise due to the tendency of initiating ART early in the life of HIV-infected individuals or those at risk of infection. Long- time exposure to different ART regimens and the potential effect of birth-defect induction in pregnancy are not completely understood. Developing regions harbor the highest numbers of women of reproductive age exposed to ART. Most of the largest and expressive data come from developed countries, and could not be sufficiently representative of pregnant women living in developing countries.

This study determined that there is no significant asso- ciation between the development of HIV-related ocular manifestation and the length of time a PLWHA had been on antiretroviral therapy so far as predisposing factors like CD4 + T cell count and age are favourable. With regards to the antiretroviral regimen in use all the participants were on first line drugs; however, those on the first line first choice option drugs (Zidovudine + Lamivudine + Nevirapine/Efavirenz) showed a higher proportion of participants (83 %) with ocular compli- cations as compared to those on the first line second choice option drugs (Tenofovir + Lamivudine + Nevirapine/ Efavirenz) who had a smaller proportion with HIV-related ocular involvement (17 %). This difference is significant with a p-value less than 0.001.

A retrospective study was conducted among antiretroviral- naïve HIV-infected patients who were initiated NVP-based ART with a fixed-dose combination of d4T, 3TC and NVP 200 mg (GPO-VIR) between October 2004 and Novem- ber 2005 at Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand. The clinical data were retrospectively reviewed and retrieved from case records. Inclusion criteria were as follows: (1) HIV-infected patients >15 years of age, (2) naïve to antiretroviral therapy, (3) were initiated with a NVP-based ART regimen, (4) used NVP 200-mg once-daily lead-in dose during the first 2 weeks, prior to escalation to 200 mg twice daily i.e. patients received a fixed-dose combination tablet in the morning time and then received separate tab- let of d4T and 3TC in the evening at 12 hours apart. The patients were excluded if baseline creatinine level was higher than 2.0 mg/ml; baseline liver aminotransferase enzyme was higher than five times of upper normal limit, or receiving a medication that has drug-drug interactions with NVP or FLU, or FLU dosage was changed during the first six weeks of antiretroviral treatment. Each eligible patient was categorized into one of the two groups accord- ing to whether the patient received FLU or not as follows: did not receive FLU (group A) or received FLU 200 mg/ day or 400 mg/day (group B). The trough plasma NVP lev- els were performed after six weeks of NVP-based ART. All patients in group B did not have the dosages of FLU changed before measurement of NVP level. Liver enzymes were monitored at 12 weeks of ART and when patients developed clinical signs and symptoms suggested for clin- ical hepatitis.

Only 2% of the patients indicated that they are members of a support group. The majority are not. Treatment and support groups are integral to patient management and the lack or non availability of the services hugely increases the risk of non psychotic psychiatric morbidities among patients receiving ART. Better ART outcomes, including higher program retention rates, may be obtained in services that have smaller numbers of patients and, therefore, that population coverage should be achieved with smaller decentralized facilities rather than a few large programs. Large programmes make it impossible to effectively decentralize patients as found out in one study evaluating ART outcomes, including higher program retention rates. The study also showed that better ART outcomes may be obtained in services that have smaller numbers of patients and therefore, that population coverage should be achieved with smaller decentralized facilities rather than a few large programs The study in question embarked on an evaluation of the Antiretroviral therapy program in Makonde district, Mashonaland West, Zimbabwe which data is Unpublished.

We acknowledge a number of limitations in our study. First, the study lacked a control group which makes it difficult to differentiate the effect of regression to the mean from the effect of cART. Second, we were not able to measure CRP concentrations at the 90-day follow-up. CRP is a strong correlate of cardiometabolic risk [3]. Third, we lacked baseline viral load values be- cause they were not part of standard of care in Zambia at the time of the study and could not be measured for the current analysis due to financial constraints. Viral load measurements are important markers of disease progression in HIV infected patients and could influ- ence response to antiretroviral therapy. However, the 3 cART regimen categories had similar CD4 cell counts (P=0.87) indicating no obvious differences in disease progression between the 3 treatment categories. Fourth, our study had a short follow-up period of 90 days, a period during which underweight or emaciated pa- tients may still be resetting their metabolic profiles fol- lowing treatment. However, the few studies in resource poor settings that have followed patients for a longer period (up to 24 months) have reported similar associ- ations [13].

transmission [4, 5-6]. Knowing that adherence to ART remains the cornerstone of undetectable viremia; thus, adherence should be currently maintained and monitored. Although adherence is described as the “behavioral bridge from efficacy to effectiveness” [5], several behavioral interventions are performed to improve adherence. However, adherence assessment in short term as well as in long term is prone to biases. Meaning, current mechanisms to measure adherence have their limitations. Self-report can be limited by recall bias, poor recollection, or a desire to please the provider (“social desirability bias”) [5, 7-8]. Even if pill counts and medication event monitoring systems (MEMS) may improve the accuracy of adherence monitoring, [5-9] neither measure can record exactly actual drug consumption [5, 7-10], nor quantify pharmacokinetic parameters [5]. Then, there is not an accurate gold measure of adherence for antiretroviral therapy. Moreover, the threshold between virological success and failure lacks precision. Clinical, immunological and virological parameters are less effective in judging treatment failure or success. Studies have shown that the prevalence of failure in patients on a second-line regimen has been reported to be as high as 33% in South African patients on LPV/r-based regimens [11]. This could be explained by lack of accurate tool in monitoring patients' adherence. The identification of patients with poor adherence can limit unnecessary genotypic ARV resistance testing (GART), which is costly, enabling GART to be reserved for those who fail despite adequate drug exposure. This selective use of GART could aid in the choice of the next optimal regimen, either through using currently available drugs, or by guiding the choice of third-line regimen agents, once newer ARVs become

Abstract: A case-cohort study, within a multi-country trial of antiretroviral therapy (ART) efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS)), was conducted to determine if pre-ART serum selenium deficiency is independently associated with human immunodeficiency virus (HIV) disease progression after ART initiation. Cases were HIV-1 infected adults with either clinical failure (incident World Health Organization (WHO) stage 3, 4 or death by 96 weeks) or virologic failure by 24 months. Risk factors for serum selenium deficiency (<85 μg/L) pre-ART and its association with outcomes were examined. Median serum selenium concentration was 82.04 μg/L (Interquartile range (IQR): 57.28–99.89) and serum selenium deficiency was 53%, varying widely by country from 0% to 100%. In multivariable models, risk factors for serum selenium deficiency were country, previous tuberculosis, anemia, and elevated C-reactive protein. Serum selenium deficiency was not associated with either clinical failure or virologic failure in multivariable models. However, relative to people in the third quartile (74.86–95.10 μg/L) of serum selenium, we observed increased hazards (adjusted hazards ratio (HR): 3.50; 95% confidence intervals (CI): 1.30–9.42) of clinical failure but not virologic failure for people in the highest quartile. If future studies confirm this relationship of high serum selenium with increased clinical failure, a cautious approach to selenium supplementation might be needed, especially in HIV-infected populations with sufficient or unknown levels of selenium.

Introduction: Despite improvements in treatment (eg, reduction in pill intake), antiretroviral therapy (ART) is dispensed in socially inef fi cient and uneconomical packaging. To make pills less conspicuous and decrease the risk of being stigmatized, people living with HIV (PLWH) often engage in self-repackaging – the practice of transferring ART from original packaging to alternative containers. This behavior has been associated with ART nonadherence and failure to achieve viral load suppression. While much of the literature on ART packaging has centered around medication adherence, patients stated preferences for ART packaging and packaging attributes that in fl uence the observed ART nonadherence are understudied.

Abstract: The development of antiretroviral drugs has significantly changed the perception of HIV/AIDS from a very fatal to a chronic and potentially manageable disease, and the avail- ability and administration of antiretroviral therapy (ART) has significantly reduced mortality and morbidity associated with HIV and AIDS. There is a relationship between ART and quality of life of people living with HIV and AIDS, and several studies have reported a strong positive association between ART and improved quality of life in different domains among people liv- ing with HIV and AIDS in both developed and developing countries. However, a few studies have reported on the negative effects of ART, which directly or indirectly relate to the quality of life and longevity of HIV-infected persons. In this review, the effects and benefits of ART on people living with HIV and AIDS based on studies done in developed and developing countries is examined.

Introduction: Successful management of pediatric and adult human immunodeficiency virus (HIV) disease includes lifelong administration of antiretroviral therapy (ART). The need for the continuous use of antiretroviral drugs throughout the life course poses a challenge to children, adolescents, and adults living with HIV and their caregivers. Historically, treatment interruptions have been viewed as a negative therapeutic strategy. Recently, however, treatment interruptions or treatment reduction strategies have become a focus of investigations as innovative approaches to the long-term management of HIV disease. Current challenges with treatment interruptions include identifying an appropriate timeframe for length of interruptions and identifying HIV patient populations in whom the treatment interruption can be successful.

Purpose: For commencement of Antiretroviral Therapy (ART), CD4 count and/or WHO clinical staging is used as the guide in India. In western countries along with clinical and immunological criteria, HIV-1 viral load is also used to start the patient on treatment. The present study was conducted to determine the role of viral load in taking decision on ART commencement in HIV-1 infected treatment naïve individuals. Method: A cross sectional study was carried out at the Integrated Counseling and Testing Centre (ICTC) in the Department of Microbiology at a Tertiary care teaching hospital after Institutional Ethics Committee approval. After obtaining written informed consent, HIV-1 infected pa- tients who were clinically asymptomatic, ART naïve, having CD4 count <250 cells/mm 3

One of the most formidable challenges in health sector is human immune deficiency virus (HIV). Once infected the human body cannot clear out this virus. Highly active antiretroviral therapy (HAART) is the name given to the treatment regimen to suppress HIV replication and progression which has lead to a remarkable reduction in the morbidity and mortality. [1] Up to 25% of patients discontinue their HAART regimen because of treatment failure, toxic effects and noncompliance with in the initial months of therapy. These medicines are associated with significant safety concerns including serious Adverse Drug Reactions (ADRs) with short and long term effects. Studies on incidence of ADRs reported that incidence rate is 10 to 40%. [2] The pattern and incidence of ADRs may vary due to economic restrictions, co morbid conditions and opportunistic infections. In India adverse drug reactions go unnoticed or are not reported. [3] Earlier antiretroviral drugs at their introduction stage are validated in white people but are now widely using in developing countries. [4] So this study was aimed to determine the incidence of clinically significant adverse events after short term fixed dose regimen in terms of their causality, severity and preventability. [5,6] Study also aimed to find out relationship between distribution of these ADRs with respect to age, sex, drug regimen, number of drugs and opportunistic infections.

The efficient inhibition of the HIV-1 life cycle by highly active antiretroviral therapy (HAART) has been shown to profoundly improve the morbidity and mortality among HIV-1–infected patients (1–4). Current routine drug regimens typically consist of various combinations of compounds that target the viral proteins reverse transcriptase, protease, and gp41 (5). Unfortunately, in a growing number of patients long-term HAART is accompanied by significant adverse side effects including mitochondrial toxicity, lipodystrophy, diabetes mellitus, and osteoporosis (5). In addition, HIV-1 can acquire resistance to all known inhibitors of reverse transcriptase, protease, and gp41, and transmission of multidrug-resistant HIV strains is becoming a growing problem among newly infected persons. In fact, a recent study reported that the proportion of new HIV infections that involve antiretroviral drug–resistant virus increased significantly in North America over the previous years (6). Therefore, it is an ongo- ing task to develop new drugs for targeting drug-resistant viruses. As multidrug-resistant viruses frequently exhibit broad cross-resistance to inhibitors of reverse transcriptase and protease, it is also impor- tant to identify new targets for inhibition of viral replication (7).

Continued progress in treatment of HIV infection depends not only on development of new antiretroviral drugs but also on complete understanding of how these drugs act. Such insight will allow for pharmacologic interventions that can further improve the action of known antiretroviral drugs. Recent experimental advances, such as the development of direct single round infection assays [4,25] that do not suffer from the unreliability of indirect or multiround assays [26,27] have provided a better understanding of the pharmaco- dynamic properties for available antiretroviral drugs. Moreover, class-specific pharmacodynamics properties that impact pharmacologic effect are now apparent as well. These properties reflected in pharmacodynamic parameters are obtained through the empirical fitting of models, such as the Michaelis-Menten or Median-Effect models of enzyme kinetics, to experimental data [10]. While these models can offer an empirical basis for understanding the pharmacodynamics and activity of antiretroviral therapy, they cannot provide mechanistic insight because HIV viral kinetics do not meet many of the important assumptions that underlie these models.