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1.  Adverse drug reactions to antiretroviral therapy (ARVs): incidence, type and risk factors in Nigeria 
Background
Data on adverse drug reactions (ADRs) related to antiretroviral (ARV) use in public health practice are few indicating the need for ART safety surveillance in clinical care.
Objectives
To evaluate the incidence, type and risk factors associated with adverse drug reactions (ADRs) among patients on antiretroviral drugs (ARV).
Methods
Patients initiated on ARVs between May 2006 and May 2009 were evaluated in a retrospective cohort analysis in three health facilities in Nigeria. Regimens prescribed include nucleoside backbone of zidovudine (AZT)/lamivudine (3TC), stavudine (d4T)/3TC, or tenofovir (TDF)/3TC in combination with either nevirapine (NVP) or efavirenz (EFV). Generalized Estimating Equation (GEE) model was used to identify risk factors associated with occurrence of ADR.
Results
2650 patients were followed-up for 2456 person-years and reported 114 ADRs (incidence rate = 4.6/100 person-years).There were more females 1706(64%) and 73(64%) of the ADRs were reported by women. Overall, 61(54%) of ADRs were reported by patients on AZT with 54(47%) of these occurring in patients on AZT/NVP. The commonest ADRs reported were pain 25(30%) and skinrash 10(18%). Most ADRs were grade 1(39%) with only 1% being life threatening (grade 4). Adjusted GEE analysis showed that ADR was less likely to occur in patients on longer duration of ART compared to the first six months on treatment; 6-12 months AOR 0.38(95% CI:0.16-0.91) and 12-24 months AOR 0.34(95% CI:0.16-0.73) respectively. Compared to patients on TDF, ADR was less likely to occur in patients on d4T and AZT AOR 0.18(95% CI 0.05-0.64) and AOR 0.24(95% CI:0.7-0.9) respectively. Age, gender and CD4 count were not significantly associated with ADRs.
Conclusion
ADRs are more likely to occur within the first six months on treatment. Close monitoring within this period is required to prevent occurrence of severe ADR and improve ART adherence. Further research on the tolerability of tenofovir in this environment is recommended.
doi:10.1186/1472-6904-12-7
PMCID: PMC3317861  PMID: 22369677
Adverse drug reactions; ADR; Antiretroviral; Zidovudine; Stavudine; Tenofovir; HIV/AIDS; Nigeria; Incidence; Risk factors
2.  HIV-1 Antiretroviral Resistance 
Drugs  2012;72(9):e1-e25.
The efficacy of an antiretroviral (ARV) treatment regimen depends on the activity of the regimen’s individual ARV drugs and the number of HIV-1 mutations required for the development of resistance to each ARV — the genetic barrier to resistance. ARV resistance impairs the response to therapy in patients with transmitted resistance, unsuccessful initial ARV therapy and multiple virological failures. Genotypic resistance testing is used to identify transmitted drug resistance, provide insight into the reasons for virological failure in treated patients, and help guide second-line and salvage therapies. In patients with transmitted drug resistance, the virological response to a regimen selected on the basis of standard genotypic testing approaches the responses observed in patients with wild-type viruses. However, because such patients are at a higher risk of harbouring minority drug-resistant variants, initial ARV therapy in this population should contain a boosted protease inhibitor (PI) — the drug class with the highest genetic barrier to resistance.
In patients receiving an initial ARV regimen with a high genetic barrier to resistance, the most common reasons for virological failure are nonadherence and, potentially, pharmacokinetic factors or minority transmitted drug-resistant variants. Among patients in whom first-line ARVs have failed, the patterns of drug-resistance mutations and cross-resistance are often predictable. However, the extent of drug resistance correlates with the duration of uncontrolled virological replication. Second-line therapy should include the continued use of a dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing backbone, together with a change in the non-NRTI component, most often to an ARV belonging to a new drug class.
The number of available fully active ARVs is often diminished with each successive treatment failure. Therefore, a salvage regimen is likely to be more complicated in that it may require multiple ARVs with partial residual activity and compromised genetic barriers of resistance to attain complete virological suppression. A thorough examination of the patient’s ARV history and prior resistance tests should be performed because genotypic and/or phenotypic susceptibility testing is often not sufficient to identify drug-resistant variants that emerged during past therapies and may still pose a threat to a new regimen. Phenotypic testing is also often helpful in this subset of patients. ARVs used for salvage therapy can be placed into the following hierarchy: (i) ARVs belonging to a previously unused drug class; (ii) ARVs belonging to a previously used drug class that maintain significant residual antiviral activity; (iii) NRTI combinations, as these often appear to retain in vivo virological activity, even in the presence of reduced in vitro NRTI susceptibility; and rarely (iv) ARVs associated with previous virological failure and drug resistance that appear to have possibly regained their activity as a result of viral reversion to wild type. Understanding the basic principles of HIV drug resistance is helpful in guiding individual clinical decisions and the development of ARV treatment guidelines.
doi:10.2165/11633630-000000000-00000
PMCID: PMC3689909  PMID: 22686620
3.  Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis 
Rhee, Soo-Yon | Blanco, Jose Luis | Jordan, Michael R. | Taylor, Jonathan | Lemey, Philippe | Varghese, Vici | Hamers, Raph L. | Bertagnolio, Silvia | de Wit, Tobias F. Rinke | Aghokeng, Avelin F. | Albert, Jan | Avi, Radko | Avila-Rios, Santiago | Bessong, Pascal O. | Brooks, James I. | Boucher, Charles A. B. | Brumme, Zabrina L. | Busch, Michael P. | Bussmann, Hermann | Chaix, Marie-Laure | Chin, Bum Sik | D’Aquin, Toni T. | De Gascun, Cillian F. | Derache, Anne | Descamps, Diane | Deshpande, Alaka K. | Djoko, Cyrille F. | Eshleman, Susan H. | Fleury, Herve | Frange, Pierre | Fujisaki, Seiichiro | Harrigan, P. Richard | Hattori, Junko | Holguin, Africa | Hunt, Gillian M. | Ichimura, Hiroshi | Kaleebu, Pontiano | Katzenstein, David | Kiertiburanakul, Sasisopin | Kim, Jerome H. | Kim, Sung Soon | Li, Yanpeng | Lutsar, Irja | Morris, Lynn | Ndembi, Nicaise | NG, Kee Peng | Paranjape, Ramesh S. | Peeters, Martine | Poljak, Mario | Price, Matt A. | Ragonnet-Cronin, Manon L. | Reyes-Terán, Gustavo | Rolland, Morgane | Sirivichayakul, Sunee | Smith, Davey M. | Soares, Marcelo A. | Soriano, Vincent V. | Ssemwanga, Deogratius | Stanojevic, Maja | Stefani, Mariane A. | Sugiura, Wataru | Sungkanuparph, Somnuek | Tanuri, Amilcar | Tee, Kok Keng | Truong, Hong-Ha M. | van de Vijver, David A. M. C. | Vidal, Nicole | Yang, Chunfu | Yang, Rongge | Yebra, Gonzalo | Ioannidis, John P. A. | Vandamme, Anne-Mieke | Shafer, Robert W.
PLoS Medicine  2015;12(4):e1001810.
Background
Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.
Methods and Findings
We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.
Conclusions
Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.
In this individual patient and sequence-level meta-analysis, Soo-Yon Rhee and colleagues measure regional trends in HIV-1 transmitted drug resistance prevalence and investigate the specific mutations responsible for TDR in different regions and in different virus subtypes.
Editors' Summary
Background
About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells and leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within ten years of infection. Then, in 1996, effective antiretroviral (ARV) therapy—drug combinations that suppress HIV replication by inhibiting reverse transcriptase and other essential viral enzymes—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ARV therapy was expensive, HIV/AIDS remained fatal in low- and middle-income countries (LMICs). In 2003, the international community began to work towards achieving universal access to ARV therapy. Now, more than 10 million HIV-positive individuals in LMICs receive ARV therapy, usually as a fixed-dose combination of two nucleoside reverse transcriptase inhibitors (NRTIs), such as tenofovir and lamivudine, plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz or nevirapine.
Why Was This Study Done?
The global scale-up of ARV therapy has reduced deaths from HIV/AIDS and the incidence of HIV infection in LMICs, but the development of resistance to ARV therapy is threatening these advances. HIV rapidly accumulates genetic changes (mutations), some of which make HIV resistant to ARV therapy. Up to 30% of patients receiving a fixed-dose NRTI/NNRTI combination develop virological failure, and a high proportion of these patients develop mutations associated with resistance to the ARVs in their regimen. Moreover, the proportion of newly infected, ARV-naïve individuals with transmitted drug resistance (TDR) is also increasing. Organizations involved in HIV/AIDS control need to understand the regional and temporal mutational patterns of TDR to inform the development of guidelines for first-line ARV therapy and of inexpensive resistance mutation assays for use in LMICs. Here, using a statistical approach called meta-analysis to combine information from individual patients about the resistance mutations they carry, the researchers investigate the molecular epidemiology of TDR (the patterns of molecular changes underlying TDR in populations) and identify the HIV drug-resistance mutations most responsible for TDR in different world regions.
What Did the Researchers Do and Find?
The researchers identified 287 studies published between 2000 and 2013 from 111 countries that included the reverse transcriptase sequences of HIV viruses from 50,870 ARV-naïve, HIV-positive individuals. The researchers analyzed each virus sequence for the presence of 93 surveillance drug-resistance mutations (SDRMs) previously shown to be specific indicators of TDR. Meta-analysis of these data indicated that the average overall prevalence of TDR (the proportion of ARV-naïve, HIV-positive individuals infected with a virus carrying one or more SDRMs) ranged from 2.8% in sub-Saharan Africa to 11.5% in North America. In sub-Saharan Africa, the odds (chance) of TDR increased 1.09-fold per year following national ARV scale-up; this increase was attributable to an increase in NRTI- and NNRTI-associated resistance. By contrast, in LMICs in south/southeast Asia, the odds of TDR remained unchanged following ARV scale-up. In Latin America/Caribbean, North America, Europe, and upper-income Asian countries, the odds of TDR have increased by around 1.10-fold per year since 1995, mainly as a result of increased NNRTI resistance. Four NNRTI-associated and 16 NRTI-associated SDRMs accounted for most NNRTI- and NRTI-associated TDR, respectively, in all regions. Notably, in sub-Saharan Africa and south/southeast Asia, most of the NNRTI-associated SDRMs detected were associated with high-level resistance to nevirapine or efavirenz. Finally, the researchers report that 95% of TDR viruses in sub-Saharan Africa and south/southeast Asia were unrelated and had therefore arisen independently.
What Do These Findings Mean?
Because many drug-resistance mutations reduce HIV’s fitness and tend to be lost rapidly in individuals not exposed to ARV therapy, differences among the datasets used in this meta-analysis with respect to how long each ARV-naïve patient had been infected with HIV before virus sampling may limit the accuracy of these findings. Nevertheless, the finding that most of the TDR strains detected in sub-Saharan Africa and south/southeast Asia arose independently suggests that improved patient adherence to ARV therapy and the use of ARV regimens that contain drugs to which HIV rarely develops resistance (regimens with a high genetic barrier to resistance) should reduce the generation of new ARV-resistant strains and mitigate TDR increases. In addition, the finding that a few NNRTI-resistance mutations were responsible for most cases of transmitted high-level resistance suggests that an inexpensive assay that detects these specific mutations may be useful for pre-therapy screening in LMICs with high TDR levels.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001810.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on antiretroviral drugs and on universal access to ARV therapy; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including its guidelines on the use of antiretroviral therapy for treating and preventing HIV infection
The UNAIDS World AIDS Day Report 2014 provides up-to-date information about the AIDS epidemic and efforts to halt it, including progress towards universal access to antiretroviral therapy
The Stanford University HIV Drug Resistance Database includes information about surveillance drug-resistant mutations (SDRMs) and an interactive map displaying HIV drug resistance in ARV-naïve populations
doi:10.1371/journal.pmed.1001810
PMCID: PMC4388826  PMID: 25849352
4.  Evolution of Antiretroviral Drug Costs in Brazil in the Context of Free and Universal Access to AIDS Treatment  
PLoS Medicine  2007;4(11):e305.
Background
Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil's AIDS treatment program has been cited widely as the developing world's largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005.
Methods and Findings
We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir–ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil's locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil's locally produced generics totaled US$110 million from 2001 to 2005.
Conclusions
Despite Brazil's more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual property regulations, epidemiological profiles, AIDS treatment guidelines, and differing capacities to produce drugs locally.
Amy Nunn and colleagues analyze the cost of antiretroviral drugs in Brazil between 2001 and 2005 and discuss the implications for HIV treatment in other developing countries.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed 29 million people since the first case occurred in 1981 and an estimated 40 million people live with HIV/AIDS today. AIDS is caused by the human immunodeficiency virus (HIV), which destroys the immune system. Infected individuals are consequently very susceptible to other infections. Early in the AIDS epidemic, most HIV-positive individuals died within a few years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a cocktail of antiretroviral drugs (ARVs)—was developed. For people who could afford HAART (which holds HIV infections in check), AIDS became a chronic disease. People who start HAART must keep taking it or their illness will progress.
Unfortunately, few people in low- and middle-income countries could afford these expensive drugs. In 2001, ARV prices fell in developing countries as AIDS activists and developing country governments challenged pharmaceutical companies about ARV prices, pharmaceutical companies set tiered prices for the low- and middle-income countries and more generic (inexpensive copies of brand-named drugs) ARVs became available. In 2003, the lack of access to HIV/AIDS treatment was declared a global health emergency. Governments, international organizations, and funding bodies began to set targets and provide funds to increase access to HAART in developing countries. By 2007, over 2 million people in low- and middle-income countries had access to HAART, but another 5 million remain in urgent need of drugs for treatment.
Why Was This Study Done?
In 1995, many countries in the world signed the World Trade Organization (WTO) Trade-Related Aspects of Intellectual Property (TRIPS) agreement, which requires countries to acknowledge intellectual property rights for many products, including pharmaceuticals. In 1996, Brazil became the first developing country to commit to and implement policies to provide free and universal access to HAART. Since then, Brazil's successful AIDS treatment program has become a model for the developing world, and 180,000 Brazilians were receiving HAART at the end of 2006. However, as a WTO member that signed on to the TRIPS agreement, Brazil was required to recognize the intellectual property rights of pharmaceutical companies' patented ARVs. As Brazil scaled up treatment in the late 1990s, the cost of treating AIDS patients rose quickly and the country took controversial public policy steps to reduce the cost of providing HAART to people living with HIV/AIDS. Brazil produces several non-patented ARVs locally, and since 2001 has challenged multinational pharmaceutical companies about the prices of patented ARVs. To induce price reductions for patented ARVs, Brazil has threatened to issue compulsory licenses (which under WTO terms allow countries facing a health emergency to produce patented drugs without consent of the company holding the patent). Brazil also recently issued a compulsory license for one ARV.
Although world leaders have set a target of universal access to HAART by 2010, little is known about the long-term costs of AIDS treatment in developing countries. In this study, the researchers have investigated how and why the costs of ARVs changed in Brazil between 2001 and 2005 and discuss the relevance of the Brazilian model for AIDS treatment for other resource-limited settings.
What Did the Researchers Do and Find?
The researchers analyzed the prices for each ARV recommended in Brazil's therapeutic guidelines for adults and estimated the changes in purchase quantities for each between 2001 and 2005. These changes likely stem from the growing number of options in Brazil's treatment guidelines, the steadily rising number of patients commencing treatment, and patients' shifts to second- and third-line treatments when their HIV infection became resistant to first-line drugs or they developed side effects. The researchers report that the generic drugs produced in Brazil were generally more expensive than similar drugs made elsewhere, but Brazil's negotiated drug prices for many patented ARVs were lower than elsewhere. Overall, total annual drug expenditure on ARVs doubled between 2001 and 2005, reaching US$414 million in 2005. Because many drug prices fell sharply as a result of declining patented drug prices over the study period, this increase was mainly attributable to increases in drug quantities purchased. If these quantities had stayed constant, the total annual cost would have increased by only $7 million, to $211 million. Conversely, without the decrease in the price of patented drugs, Brazil would have spent $952 million annually by 2005. If Brazil had enjoyed the lowest global prices for generic medicines, the total costs per year in 2005 would have been $367 million, or nearly $50 million less than the costs Brazil actually realized.
What Do These Findings Mean?
These findings tease out the many factors—clinical, commercial, and political—that affected the total costs of the Brazilian AIDS treatment program between 2001 and 2005.
Brazil's ability to produce generic drugs facilitated Brazil's price negotiations for patented drugs. Although Brazil saved approximately US$1 billion over the study period as a result of declining prices for patented medicines, the cost of producing generic drugs locally has risen while the prices for generic drugs have fallen elsewhere. Brazil's recent decision to import a generic ARV using a compulsory license suggests that the Brazilian model for AIDS treatment continues to evolve.
Questions remain about the precise causes of year-to-year cost trends in Brazil because, for example, the researchers did not have full data on when patients switched from first-line to second- or third-line drugs. The observed steep rise in costs from 2004 to 2005 in particular warrants further analysis. In addition, the findings may not be generalizable to countries with different policies on HIV/AIDS treatment, different access to generic drugs, or different bargaining power with multinational drug companies. Nevertheless, the trends this study highlights provide important information about how AIDS treatment costs are likely to evolve in other developing countries as efforts are made to provide universal access to life-saving ARVs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040305.
Information from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information from the US Centers for Disease Control and Prevention on global HIV/AIDS topics (in English and Spanish)
HIV InSite, comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco
Information from Avert, an international AIDS charity, on HIV and AIDS in Brazil and on HIV/AIDS treatment and care, including universal access to ARVs
Progress towards universal access to HIV/AIDS treatment, the latest report from the World Health Organization (available in several languages)
The National STD and AIDS Program of Brazil
doi:10.1371/journal.pmed.0040305
PMCID: PMC2071936  PMID: 18001145
5.  The impact of a HIV prevention of mother to child transmission program in a nigerian early infant diagnosis centre 
Background:
Mothers infected with human immunodeficiency virus (HIV) can transmit the virus to their babies in utero, intrapartum or postpartum through breastfeeding. Maternal to child transmission can be prevented through administration of antiretroviral drugs to mother and child, and through restriction of breastfeeding. This study evaluated the effectiveness of prevention of mother-to-child transmission (PMTCT) activities in reducing the incidence of HIV infection among exposed babies at the National Hospital Abuja, Nigeria.
Materials and Methods:
Early infant diagnosis laboratory records of 515 exposed babies aged below 18 months who had polymerase chain reaction (PCR) test between January 1st 2011 and December 31st 2012 were reviewed. The details of antiretroviral (ARV) therapy commencement for mother and baby, infant feeding choices, mode of delivery and HIV test results were analysed.
Results:
Of the 515 samples tested, 36 (7.0%) were found to be positive. The mean age of exposed children tested was 4 months. Highest prevalence was among children in the age group 6-18 months (16.1%). There was statistically significant association between HIV positive results and age. (P = 0.0000). If the mother and child pairs received ARVs, the prevalence was 1.3%, whereas if the mother only received ARV, then the prevalence was 4.6%, and when only the child received ARV the prevalence was 20.0%. When neither the mother nor the child received ARVs, the prevalence was 66.7%.
Conclusion:
There was a high prevalence of HIV among exposed children in our setting, especially if the mother and child pairs did not receive any form of antiretroviral prophylaxis. This further emphasises the usefulness of ARVs as the single most important intervention in PMTCT. Therefore, there is need to expand antiretroviral coverage, ensure access of the PMTCT program, and provide effective services to support infected children.
doi:10.4103/0300-1652.132039
PMCID: PMC4089047  PMID: 25013250
Abuja; early infant diagnosis; HIV; prevention of mother-to-child transmission
6.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
7.  HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis 
PLoS Medicine  2011;8(3):e1000430.
Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.
Background
Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.
Methods and Findings
All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR–positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).
Conclusions
Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.
Trial Registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 2 million children are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), and half a million children are newly infected every year. These infections are mainly the result of mother-to-child transmission (MTCT) of HIV during pregnancy, labor and delivery, or through breastfeeding. MTCT can be greatly reduced by treating HIV-positive mothers and their babies with antiretroviral drugs (ARVs). Without ARVs, up to half of babies born to HIV-positive mothers become infected with HIV. This rate of transmission falls to below 5% if a combination of three ARVs is given to the mother throughout pregnancy. Unfortunately, this triple-ARV therapy is too expensive for use in the resource-limited countries where most MTCT occurs. Instead, many such countries have introduced simpler, shorter ARV regimens such as a daily dose of zidovudine (a nucleoside reverse transcriptase inhibitor or NRTI) given to HIV-positive women during late pregnancy coupled with single-dose nevirapine (a non-nucleoside reverse transcriptase inhibitor or NNRTI) at the onset of labor, zidovudine and lamivudine (another NRTI) during labor and delivery, and single-dose nevirapine given to the baby at birth.
Why Was This Study Done?
More than 95% of HIV-exposed children are born in resource-limited settings where breastfeeding is the norm and is crucial for child survival even though it poses a risk of HIV transmission. Consequently, several recent studies have investigated whether MTCT can be further reduced by giving the mother ARVs while she is breastfeeding. In the Kisumu Breastfeeding Study (KiBS), for example, researchers assessed the effects of giving zidovudine, lamivudine, and either nevirapine or nelfinavir (a protease inhibitor) to HIV-infected women from 34 weeks of pregnancy through 6 months of breastfeeding. The results of KiBS indicate that this approach might be a safe, feasible way to reduce MTCT (see the accompanying paper by Thomas and colleagues). However, low amounts of nevirapine and lamivudine are transferred from mother to infant in breast milk and this exposure to ARVs could induce the development of resistance to ARVs among HIV-infected infants. In this KiBS substudy, the researchers investigate whether HIV drug resistance emerged in any of the HIV-positive infants in the parent study.
What Did the Researchers Do and Find?
In KiBS, 32 infants were HIV-positive at 24 months old; 24 were HIV-positive at 6 months old when their mothers stopped taking ARVs and when breastfeeding was supposed to stop. The researchers analyzed blood samples taken from these infants at various ages and from their mothers for the presence of HIV drug resistance mutations (DNA changes that make HIV resistant to killing by ARVs). They detected no resistance mutations in samples taken from 2-week old HIV-positive infants or from the infants who became infected after the age of 6 months. However, they found resistance mutations in a third and two-thirds of samples taken from 6-week and 6-month old HIV-positive infants, respectively. The commonest mutations conferred resistance to lamivudine and nevirapine. Moreover, resistance mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half those taken from infants whose mothers who had received nevirapine. Finally, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations.
What Do These Findings Mean?
These findings indicate that, in this KiBS substudy, the emergence of HIV drug resistance mutations in HIV-infected infants whose mothers were receiving ARVs occurred between 2 weeks and 6 months after birth. The pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through MTCT of drug-resistant virus. These findings need confirming but suggest that infants exposed to ARVs through breast milk—a situation that may become increasingly common given the reduction in MTCT seen in KiBS and other similar trials—should be carefully monitored for HIV infection. Providers should consider the mothers' regimen when choosing treatment for infants who are found to be HIV-infected despite maternal triple drug prophylaxis. Infants exposed to a maternal regimen with NNRTI drugs should receive first-line therapy with lopinavir/ritonavir, a protease inhibitor. The significance of the NRTI mutations such as M184V with regard to response to therapy needs further evaluation. The M184V mutation may result in hypersensitization to other NRTI drugs and delay or reverse zidovudine resistance. Given the limited availability of alternative drugs for infants in resource-limited settings, provision of the standard WHO-recommended first-line NRTI backbone, which includes 3TC, with enhanced monitoring of the infant to ensure virologic suppression, could be considered. Such an approach should reduce both illness and morbidity among infants who become HIV positive through breastfeeding.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000430.
The accompanying PLoS Medicine Research article by Thomas and colleagues describes the primary findings of the Kisumu Breastfeeding Study
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV (in several languages), and guidance on the use of ARVs for preventing MTCT
doi:10.1371/journal.pmed.1000430
PMCID: PMC3066134  PMID: 21468304
8.  Acceptability and confidence in antiretroviral generics of physicians and HIV-infected patients in France 
Journal of the International AIDS Society  2014;17(4Suppl 3):19608.
Introduction
Switching brand name medications to generics is recommended in France in the interest of cost effectiveness but patients and physicians are sometimes not convinced that switching is appropriate. Some antiretroviral (ARV) generics (ZDV, 3TC, NVP) have been marketed in France since 2013.
Materials and Methods
A multicentric cross-sectional survey was performed in September 2013 to evaluate the perception of generics overall and ARV generics in physicians and HIV-infected patients and factors associated to their acceptability. Adult HIV outpatients were asked to complete a self-questionnaire on their perception of generics. Physicians completed a questionnaire on the acceptability of generics and ARV generics. Socio-demographic data, medical history and HIV history were collected.
Results
116 physicians in 33 clinics (68% in University Hospital) included 556 patients (France-native 77%, active employment 59%, covered by social Insurance 100%, homosexual/bisexual contamination 47%, median HIV duration 13 years, hepatitis coinfection 16%, on ARV therapy 95%). Overall, patients accepted and had confidence in generics in 76% and 55% of the cases, respectively. Switching ARVs for generics was accepted by 44% of the patients but only by 17% if the pill burden was going to increase. 75% of the physicians would prescribe generics, but this decreased to only 26% if the combo had to be broken. The main reasons for non-prescription of generics were previous brand name ARV-induced side effects (35%), refusal of generics overall (37%), lack of understanding of generics (26%), risk of non-observance of treatment (44%), anxiety (47%) and depressive symptoms (25%). In multivariate analysis, factors associated with the acceptability of ARV generics in patients were the use of generics overall (p<0.001) and in physicians, the absence of concern regarding the drug efficacy (p<0.001) and being aware that the patient would accept generics overall (p=0.03) and ARV generics (p=0.04). No factors related to sociodemographic conditions, HIV status or comorbidities had a constrictive influence on the use of ARV generics.
Conclusion
Acceptability of ARV generics in this French population is mostly dictated by the patient's and physician's knowledge and use of generics overall. Switching ARV brand name to a generic would be better accepted if the pill burden remained unchanged.
doi:10.7448/IAS.17.4.19608
PMCID: PMC4224798  PMID: 25394112
9.  A clinically useful risk-score for chronic kidney disease in HIV infection 
Journal of the International AIDS Society  2014;17(4Suppl 3):19514.
Introduction
Development of a simple, widely applicable risk score for chronic kidney disease (CKD) allows comparisons of risks or benefits of starting potentially nephrotoxic antiretrovirals (ARVs) as part of a treatment regimen.
Materials and Methods
A total of 18,055 HIV-positive persons from the Data on Adverse Drugs (D:A:D) study with >3 estimated glomerular filtration rates (eGFRs) >1/1/2004 were included. Persons with use of tenofovir (TDF), atazanavir (ritonavir boosted (ATV/r) and unboosted (ATV)), lopinavir (LPV/r) and other boosted protease inhibitors (bPIs) before baseline (first eGFR >60 ml/min/1.73 m2 after 1/1/2004) were excluded. CKD was defined as confirmed (>3 months apart) eGFR <60. Poisson regression was used to develop a score predicting low (<0 points), medium (1–4 points) and high (>5 points) risk of developing CKD. Increased incidence of CKD associated with starting ARVs was modelled by including ARVs as time-updated variables. The risk score was externally validated on two independent cohorts.
Results
A total of 641 persons developed CKD during 103,278.5 PYFU (incidence 6.2/1000 PYFU, 95% CI 5.7–6.7). Older age, intravenous drug use, HCV+ antibody status, lower baseline eGFR, female gender, lower CD4 nadir, hypertension, diabetes and cardiovascular disease predicted CKD and were included in the risk score (Figure 1). The incidence of CKD in those at low, medium and high risk was 0.8/1000 PYFU (95% CI 0.6–1.0), 5.6 (95% CI 4.5–6.7) and 37.4 (95% CI 34.0–40.7) (Figure 1). The risk score showed good discrimination (Harrell's c statistic 0.92, 95% CI 0.90–0.93). The number needed to harm (NNTH) in patients starting ATV or LPV/r was 1395, 142 or 20, respectively, among those with low, medium or high risk. NNTH were 603, 61 and 9 for those with a low, medium or high risk starting TDF, ATV/r or bPIs. The risk score was externally validated on 2603 persons from the Royal Free Hospital clinic cohort (94 events, incidence 5.1/1000 PYFU; 95% CI 4.1–6.1) and 2013 persons from the control arms of SMART/ESPRIT (32 events, incidence 3.8/1000 PYFU; 95% CI 2.5–5.1). External validation showed consistent CKD rates across risk groups (Figure 2).
Interpretation
Traditional and HIV-related risk factors were predictive of CKD; all are routinely available, making the risk score easy to incorporate into clinical practise and of direct relevance for clinical decision making. NNTH in persons starting potentially nephrotoxic ARVs at high risk of CKD were low, and alternative ARVs may be more appropriate.
doi:10.7448/IAS.17.4.19514
PMCID: PMC4224906  PMID: 25394023
10.  Outcomes in a Cohort of Women Who Discontinued Maternal Triple-Antiretroviral Regimens Initially Used to Prevent Mother-to-Child Transmission during Pregnancy and Breastfeeding—Kenya, 2003–2009 
PLoS ONE  2014;9(4):e93556.
Background
In 2012, the World Health Organization (WHO) amended their 2010 guidelines for women receiving limited duration, triple-antiretroviral drug regimens during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV (tARV-PMTCT) (Option B) to include the option to continue lifelong combination antiretroviral therapy (cART) (Option B+). We evaluated clinical and CD4 outcomes in women who had received antiretrovirals for prevention of mother-to-child transmission and then discontinued antiretrovirals 6-months postpartum.
Methods and Findings
The Kisumu Breastfeeding Study, 2003–2009, was a prospective, non-randomized, open-label clinical trial of tARV-PMTCT in ARV-naïve, Kenyan women. Women received tARV-PMTCT from 34 weeks' gestation until 6-months postpartum when women were instructed to discontinue breastfeeding. Women with CD4 count (CD4) <250cells/mm3 or WHO stage III/IV prior to 6-months postpartum continued cART indefinitely. We estimated the change in CD4 after discontinuing tARV-PMTCT and the adjusted relative risk [aRR] for factors associated with declines in maternal CD4. We compared maternal and infant outcomes following weaning–when tARV-PMTCT discontinued–by maternal ARV status through 24-months postpartum. Compared with women who continued cART, discontinuing antiretrovirals was associated with infant HIV transmission and death (10.1% vs. 2.4%; P = 0.03). Among women who discontinued antiretrovirals, CD4<500 cells/mm3 at either initiation (21.8% vs. 1.5%; P = 0.002; aRR: 9.8; 95%-confidence interval [CI]: 2.4–40.6) or discontinuation (36.9% vs. 8.3%; P<0.0001; aRR: 4.4; 95%-CI: 1.9–5.0) were each associated with increased risk of women requiring cART for their own health within 6 months after discontinuing.
Conclusions
Considering the serious health risks to the woman's infant and the brief reprieve from cART gained by stopping, every country should evaluate the need for and feasibility to implement WHO Option B+ for PMTCT. Evaluating CD4 at antiretroviral initiation or 6-months postpartum can identify pregnant women who would most benefit from continuing cART in settings unable to implement WHO Option B+.
doi:10.1371/journal.pone.0093556
PMCID: PMC3986059  PMID: 24733021
11.  Pharmacoepidemiology of Antiretroviral Drugs in a Teaching Hospital in Lagos, Nigeria 
Ghana Medical Journal  2014;48(4):194-203.
Summary
Objective
Prescribing, adherence, and adverse drug events to HAART in a large antiretroviral programme in Lagos was evaluated.
Design
A retrospective 5 year open cohort study
Setting
The AIDS Prevention Initiative in Nigeria (APIN) clinic at LUTH is one of the United States Presidential Emergency Plan for AIDS Relief (PEP-FAR) funded centers for HIV relief program in Nigeria Participants The case files of 390 patients on HAART and attending the APIN clinic were reviewed sequel to random selection.
Main outcome measures
Demographics of the patients and pattern of antiretroviral (ARV) combination drugs prescribed were extracted from their case files. The details of the adverse drug events (ADEs) were extracted from drug toxicity forms regularly filled for each patient. A Chi-square test with Yates correction was used to determine the association between adherence and therapeutic outcome
Results
A total of 2944 prescriptions were assessed. Zidovudine + lamivudine + nevirapine (35.87%) and stavudine + lamivudine + nevirapine (35.63%) were the most frequently prescribed combinations. Over 2000 ADEs were reported with cough (13.3%), fever (8.75%) and skin rashes (8.01%) being the most frequently reported. Drug adherence was associated with good therapeutic outcome (χ2 = 115.60, p<0.0001).
Conclusions
Zidovudine + lamivudine + nevirapine was the most frequently prescribed ARV combination. Cough was the most frequently reported ADE. Interventions aimed at rational prescribing of ARV drugs and improving adherence to antiretroviral drugs is essential for good therapeutic outcome in the treatment of HIV infection.
PMCID: PMC4335432  PMID: 25709134
Pharmacoepidemiology; antiretroviral drugs; drug adherence; adverse events
12.  Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial 
PLoS Medicine  2011;8(3):e1001015.
Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study (Kenya), a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.
Background
Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.
Methods and Findings
HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34–36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load.
Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm3 were 8.4% (95% confidence interval [CI] 5.8%–12.0%) and 4.1% (1.8%–8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%–7.8%) and 8.7% (6.1%–12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%–19.4%).
Conclusions
This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.
Trial registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about half a million children become infected with human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). Nearly all these newly infected children live in resource-limited countries and most acquire HIV from their mother, so-called mother-to-child transmission (MTCT). Without intervention, 25%–50% of babies born to HIV-positive mothers become infected with HIV during pregnancy, delivery, or breastfeeding. This infection rate can be reduced by treating mother and child with antiretroviral (ARV) drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to her baby soon after birth nearly halves the risk of MTCT. Further reductions in risk can be achieved by giving mother and baby three ARVs—an NNRTI and two nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and lamivudine)—during pregnancy and perinatally (around the time of birth).
Why Was This Study Done?
Breastfeeding is crucial for child survival in poor countries but it is also responsible for up to half of MTCT. Consequently, many researchers are investigating how various ARV regimens given to mothers and/or their infants during the first few months of life as well as during pregnancy and perinatally affect MTCT. In this single-arm trial, the researchers assess the feasibility and safety of using a triple-ARV regimen to suppress the maternal HIV load (amount of virus in the blood) from late pregnancy though 6 months of breastfeeding among HIV-positive women in Kisumu, Kenya, and ask whether this approach achieves a lower HIV transmission rate than other ARV regimens that have been tested in resource-limited settings. In a single-arm trial, all the participants are given the same treatment. By contrast, in a “randomized controlled” trial, half the participants chosen at random are given the treatment under investigation and the rest are given a control treatment. A randomized controlled trial provides a better comparison of treatments than a single-arm trial but is more costly.
What Did the Researchers Do and Find?
In the Kisumu Breastfeeding Study (KiBS), HIV-infected pregnant women took a triple-ARV regimen containing zidovudine and lamivudine and either nevirapine or the protease inhibitor nelfinavir from 34–36 weeks of pregnancy to 6 months after delivery. They were advised to breastfeed their babies (who received single-dose nevirapine at birth), and to wean them rapidly just before 6 months. The researchers then used Kaplan-Meier statistical methods to estimate HIV transmission and death rates among 487 live-born infants from delivery to 24 months. The cumulative HIV transmission rate rose from 2.5% at birth to 7.0% at 24 months. The cumulative HIV transmission or death rate at 24 months was 15.7%; no infant deaths were attributed to ARVs. At 24 months, 3.0% of babies born to mothers with a low viral load were HIV positive compared to 8.7% of babies born to mothers with a high viral load, a statistically significant difference. Similarly, at 24 months, 8.4% of babies born to mothers with low baseline CD4 cell counts (CD4 cells are immune system cells that are killed by HIV; CD4 cell counts indicate the level of HIV-inflicted immune system damage) were HIV positive compared to 4.1% of babies born to mothers with high baseline CD4 cell counts, although this difference did not achieve statistical significance.
What Do These Findings Mean?
Although these findings are limited by the single-arm design, they support the idea that giving breastfeeding women a triple-ARV regimen from late pregnancy to 6 months is a safe, feasible way to reduce MTCT in resource-limited settings. The HIV transmission rates in this study are comparable to those recorded in similar trials in other resource-limited settings and are lower than MTCT rates observed previously in Kisumu in a study in which no ARVs were used. Importantly, the KiBS mothers took most of the ARVs they were prescribed and most stopped breastfeeding by 6 months as advised. The intense follow-up employed in KiBS may be partly responsible for this good adherence to the trial protocol and thus this study's findings may not be generalizable to all resource-limited settings. Nevertheless, they suggest that a simple triple-ARV regimen given to HIV-positive pregnant women regardless of their baseline CD4 cell count can reduce MTCT during pregnancy and breastfeeding in resource-limited setting.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001015.
The accompanying PLoS Medicine Research article by Zeh and colleagues describes the emergence of resistance to ARVs in KiBS
Information on HIV and AIDS is available from the US National Institute of Allergy and Infectious Diseases
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV http://www.who.int/hiv/topics/mtct/en/index.html (in several languages)
doi:10.1371/journal.pmed.1001015
PMCID: PMC3066129  PMID: 21468300
13.  Stigmatizing attitudes and low levels of knowledge but high willingness to participate in HIV management: A community-based survey of pharmacies in Pune, India 
BMC Public Health  2010;10:517.
Background
The World Health Organization (WHO) recommends that the role of pharmacists in low-income settings be expanded to address the increasing complexity of HIV antiretroviral (ARV) and co-infection drug regimens. However, in many such settings including in India, many pharmacists and pharmacy workers are often neither well trained nor aware of the intricacies of HIV treatment. The aims of our study were; to determine the availability of ARVs, provision of ARVs, knowledge about ARVs, attitudes towards HIV-infected persons and self-perceived need for training among community-based pharmacies in an urban area of India.
Methods
We performed a survey of randomly selected, community-based pharmacies located in Pune, India, in 2004-2005 to determine the availability of ARVs at these pharmacies, how they were providing ARVs and their self-perceived need for training. We also assessed knowledge, attitudes and perceptions on HIV and ARVs and factors associated with stocking ARVs.
Results
Of 207 pharmacies included in the survey, 200 (96.6%) were single, private establishments. Seventy-three (35.3%) pharmacies stocked ARVs and 38 (18.4%) ordered ARVs upon request. The reported median number of ARV pills that patients bought at one time was 30, a two week supply of ARVs (range: 3-240 pills). Six (2.9%) pharmacy respondents reported selling non-allopathic medicines (i.e. Ayurvedic, homeopathy) for HIV. Ninety (44.2%) pharmacy respondents knew that ARVs cannot cure HIV, with those stocking ARVs being more likely to respond correctly (60.3% vs. 34.8%, p = 0.001). Respondents of pharmacies which stocked ARVs were also more likely to believe it was a professional obligation to provide medications to HIV-infected persons (91.8% vs. 78.8%, p = 0.007) but they were also more likely to believe that HIV-infected persons are unable to adhere to their medicines (79.5% vs. 40.9%, p < 0.01). Knowledge of the most common side effects of nevirapine, abnormal liver enzyme profile and skin rash, was reported correctly by 8 (3.9%) and 23 (11.1%) respondents, respectively. Seven (3.4%) respondents reported that they had received special training on HIV, 3 (1.5%) reported receipt of special training on ART and 167 (80.7%) reported that they believed that pharmacy staff should get special training on ART.
Conclusion
There is a high willingness to participate in HIV management among community-based pharmacies but there is a tremendous need for training on HIV therapies. Furthermore, stigmatizing attitudes towards HIV-infected persons persist and interventions to reduce stigma are needed, particularly among those that stock ARVs.
doi:10.1186/1471-2458-10-517
PMCID: PMC2939646  PMID: 20799948
14.  Cardiovascular Disease in HIV Infection 
Current opinion in HIV and AIDS  2011;6(4):266-271.
Purpose of Review
Highly active antiretroviral therapy (HAART) use has markedly reduced AIDS-related mortality and opportunistic illness. With improved survival, cardiovascular disease (CVD) has emerged as an important non-infectious chronic co-morbidity among antiretroviral (ARV)-treated HIV-infected persons.
Recent Findings
HIV infection can impact CVD and co-morbidiities known to increase CVD risk. Untreated HIV can cause proatherogenic elevations in serum lipids. Chronic HIV viremia results in increases in systemic inflammation, hypercoagulation, and reductions in endovascular reactivity, all of which are at least partially reversible with virally suppressive HAART. Chronic T cell activation can also result in adverse vascular effects. Use of some ARV drugs can impact CVD risk by causing pro-atherogenic serum lipid elevations, induction of insulin resistance, increases in visceral adiposity or subcutaneous fat loss. Abacavir use may increase myocardial infarction risk by reducing vascular reactivity and/or increasing platelet activation. Traditional risk factors such as advancing age, smoking, hyperlipidemia, and hypertension remain important predictors of CVD among HAART-treated HIV-infected persons.
Summary
HIV in the HAART era is a chronic manageable condition. CVD is an important cause of morbidity among HIV-infected persons. Untreated HIV can increase CVD risk in several ways and these effects are at least partially reversible with successful treatment. Use of specific ARV’s can adversely impact CVD risk but the multiple long-term benefits of chronic HIV suppression and immune reconstitution achievable with potent HAART outweigh the adverse impact upon CVD risks that they may have. Standard CVD screening and risk-reducing interventions should be routinely undertaken for HIV-infected persons.
doi:10.1097/COH.0b013e328347876c
PMCID: PMC3501268  PMID: 21546831
Cardiovascular disease in HIV infection; Inflammation; hypercoagulation; vascular functioning; Effects of antiretroviral drugs; Hyperlipidemia
15.  Antiretroviral Exposure During Pregnancy and Adverse Outcomes in HIV-exposed Uninfected Infants and Children Using a Trigger-based Design: The SMARTT Study 
AIDS (London, England)  2016;30(1):133-144.
Objective
To evaluate the safety of in utero antiretroviral (ARV) exposure in children born to mothers with HIV, using a trigger-based design.
Design
The Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites to evaluate safety of in utero ARV drug exposure in HIV-uninfected children born to HIV-infected mothers. Children meeting pre-defined clinical or laboratory thresholds have more intensive evaluations to determine whether they meet criteria for adverse events (AEs).
Methods
AE “cases” were defined for the following domains: growth, hearing, language, neurology, neurodevelopment, metabolic, hematologic/clinical chemistry and blood lactate. We used adjusted log-binomial models to calculate relative risks (RR) of case status overall and within individual domains for various ARV exposures during pregnancy.
Results
Among 2680 youth enrolled between 2007 and 2012 (48% female, 66% black, 33% Hispanic), 48% met a trigger and 25% were defined as a case in at least one domain. Language (13.2%) and metabolic (11.4%) cases were most common. After adjustment for birth cohort and other factors, there was no association of any ARV regimen, drug class, or individual drug with meeting overall case criteria (case in any domain). Within individual domains, zidovudine (74% exposed) was associated with increased risk of metabolic case (RR=1.69, 95% CI:1.08–2.64) and didanosine plus stavudine (<1% exposed) with increased risk of both neurodevelopmental (RR=12.4, 95% CI:5.29–29.08) and language (RR=4.84, 95% CI:1.14–20.51) cases.
Conclusions
Our findings support current recommendations for combination ARV therapy during pregnancy, although higher risk of metabolic disorder with zidovudine exposure warrants further study.
doi:10.1097/QAD.0000000000000916
PMCID: PMC4704129  PMID: 26731758
Antiretroviral; HIV-exposed; safety; infants; mitochondrial dysfunction
16.  The suspected unexpected and serious adverse events of antiretroviral drugs used as HIV prophylaxis in HIV uninfected persons 
Journal of the International AIDS Society  2014;17(4Suppl 3):19733.
Introduction
With increased usage of antiretroviral drugs (ARVs) in HIV uninfected persons proper reporting on suspected unexpected serious adverse reactions (SUSARs) and continued insight into serious adverse events (SAEs) is needed for adequate information on ARVs safety in such populations.
Methods
We have evaluated medical documentation of persons receiving ARVs after non-occupationally HIV exposure (nPEP) during five concomitant years (2009–2013). SAEs and SUSARs were evaluated by two HIV physicians and defined according to international standards. In statistical methods, Kaplan Meier survival analysis was used to estimate the probability of SAE and Cox proportional hazard models to identify independent predictors of developing SAE. Only the first SAE was included in these analyses.
Results
In total, 375 persons received nPEP. The most common reason was needle stick (43%), followed by unprotected sexual intercourse (17%), rape (10%) and first aid (10%). In 84 (22%) cases, the source patient was either known to be HIV positive or within a high risk group (active injecting drug user). In total, 170 SAEs were reported, 139 persons had only one SAE and majority developed it within first two weeks. The most frequent first SAEs were gastrointestinal disorders (22%), followed by general symptoms (9%), hypersensitivity reactions (1.6%) and CNS symptoms (1.3%). The remaining events were laboratory abnormalities of liver and kidney function, haematological disorders, other and unknown, each contributing to less than 1% of all patients. 8 (2.1%) patients have developed a SUSAR (bradycardia, vivid dreams, lymphadenopathy of the neck, increased platelet count, swelling and pain of large joints, swelling of lower limbs, peripheral oedema and loss of concentration). 22 (5.9%) persons discontinued nPEP due to adverse event and 19 (5.1%) required a paid sick leave from work. In multivariate analyzes, only age was independent predictor of developing SAE (HR 1.17; [95% CI 1.03–1.34]; p=0.02).
Conclusions
In our observation, SAEs in reaction to nPEP were frequent yet usually mild events, mostly occurring in first two weeks and rarely causing discontinuation. The only significant factor increasing the risk of SAE was age. SUSARs were rare and moderately significant. More insight into this important area is required in order to ascertain proper pharmacovigilance of ARVs usage in HIV uninfected persons.
doi:10.7448/IAS.17.4.19733
PMCID: PMC4225290  PMID: 25397479
17.  The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs 
The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated.
doi:10.3389/fimmu.2016.00199
PMCID: PMC4876360  PMID: 27242802
HIV exposure; in utero; children; safety; toxicity; antiretroviral drugs; infant; newborn
18.  Adherence in the treatment of patients with extensively drug-resistant tuberculosis and HIV in South Africa: A prospective cohort study 
Objective
Extensively drug-resistant tuberculosis (XDR-TB)/HIV co-infection is difficult to treat with frequent adverse drug reactions, and high mortality. Adherence to antiretroviral therapy (ARV) and second-line TB medications may reduce mortality, prevent amplification of drug-resistance, and improve outcomes.
Methods
Prospective cohort study of XDR-TB patients on treatment in KwaZulu-Natal, South Africa. Adherence to ARV and TB medications was assessed separately at baseline and monthly. Knowledge, attitudes, and beliefs (KAB) were assessed at baseline. Optimal adherence was defined as self-report of taking all pills in the previous 7 days; missing any pills was defined as suboptimal adherence. Primary outcome was optimal adherence 6 months after initiation of XDR-TB treatment to TB medications, ARV, and both (‘dual-adherence’).
Results
104 XDR-TB patients (79.8% HIV co-infected, 84.3% on ARV at enrollment) were enrolled and followed monthly (median 8 visits; IQR 4–12). Six-month optimal adherence was higher for ARV (88.2%) than TB medications (67.7%) (p<0.001). Low educational attainment, male gender, and year of enrollment were independently associated with dual suboptimal adherence. At baseline participants indicated that XDR-TB was curable (76.0%), HIV and TB were linked (81.7%), and ARV improves TB outcomes (72.1%). Baseline KAB did not predict subsequent adherence.
Conclusions
Medication adherence was significantly higher for ARV than for TB medications in this cohort. Short course treatment regimens for drug-resistant TB with lower pill burden may increase adherence and improve outcomes in XDR-TB/HIV. Programmatic support for dual-adherence is critical in the treatment of drug-resistant TB and HIV.
doi:10.1097/QAI.0000000000000221
PMCID: PMC4410008  PMID: 24872138
Extensively Drug-resistant Tuberculosis; HIV/AIDS; Adherence; Knowledge; Attitudes and Beliefs
19.  The Role of Toxicity-Related Regimen Changes in the Development of Antiretroviral Resistance 
Abstract
In an effort to evaluate factors associated with the development of antiretroviral (ARV) resistance, we assessed the prevalence of toxicity-related regimen changes and modeled its association to the subsequent development of ARV resistance in a cohort of treatment-naive individuals initiating ARV therapy (ART). A retrospective analysis of patients initiating ART was conducted at the UAB 1917 Clinic from 1 January 2000 to 30 September 2007. Cox proportional hazards models were fit to identify factors associated with the development of resistance to ≥1 ARV drug class. Among 462 eligible participants, 14% (n=64) developed ARV resistance. Individuals with ≥1 toxicity-related regimen change (HR=3.94, 95% CI=1.09–14.21), initiating ART containing ddI or d4T (4.12, 1.19–14.26), and from a minority race (2.91, 1.16–7.28) had increased risk of developing resistance. Achieving virologic suppression within 12 months of ART initiation (0.10, 0.05–0.20) and higher pretreatment CD4 count (0.85 per 50 cells/mm3, 0.75–0.96) were associated with decreased hazards of resistance. Changes in ART due to drug intolerance were associated with the subsequent development of ARV resistance. Understanding the role of ARV drug selection and other factors associated with the emergence of ARV resistance will help inform interventions to improve patient care and ensure long-term treatment success.
doi:10.1089/aid.2010.0291
PMCID: PMC3192056  PMID: 21342052
20.  An assessment of adverse drug reactions among HIV positive patients receiving antiretroviral treatment in South Africa 
Background
Antiretroviral treatment (ART) has been effective in reducing HIV/AIDS related morbidity and mortality. However, the use and uptake of ART has resulted in adverse reactions, due mainly to the medicine’s toxicity and interactions with other medicines. The timing of adverse drug reactions (ADRs) among these patients is a critical public health issue for antiretroviral (ARV) treatment adherence and retention. Reliable monitoring of HIV patients on ART is through a structured pharmacovigilance surveillance system. However, recurrent nature of these data pose challenges in their analyses. This study aimed at modelling the timing of ADR events in HIV patients on ART using correlated time-to-event models.
Methods
The data concern 590 HIV patients registered onto the Medunsa National ARV Pharmacovigilance Surveillance System within 6 months of ART initiation between February 2007 and July 2011. Recurrent times of ADRs and baseline characteristics: patient gender, and age, ART regimen, clinic and initiation period were extracted from the data. The recurrent ADR events data were modelled using both shared frailty and marginal models on the five patients’ characteristics as covariates.
Results
Out of 590 patients, 67% were female, 68% started on regimen: Stavudine, Lamivudine and Efavirenz; 37% had experienced at least one ADR and 67% started ART in 2009–2011. Age (p-value = 0.0210), clinic (p-value < 0.0001) and period of ART initiation (p-value = 0.0002) were significantly associated with timing of first ADR. There was a significantly higher rates of ADR recurrences in patients aged 38–44 years [HR = 2.45; 95% CI = (1.47; 4.10)] vs. 30 years and less, patients taking regimen: Zidovudine, Lamivudine and Nevarapine) vs. regimen: Stavudine, Lamivudine and Efavirenz [HR = 2.09; 95% CI = (1.35; 3.22)], while the rate was lower among those who started ART in 2009–2011 vs. those who initiated in 2007–2008 [HR = 0.55; 95% CI = (0.40; 0.76)].
Conclusion
More realistic time-to-event models for recurrent events data have been used to analyse timing of ADR events in HIV patients taking ARV treatment. Age, antiretroviral regimen type and period of initiation of ART were associated with the timing of HIV/AIDS drug related adverse reactions regardless of the analysis model used. This study has public health policy implications in addressing the added morbidity among HIV patients taking ARV treatment in the context of universal scaling up of ARV treatment.
doi:10.1186/s12981-015-0044-0
PMCID: PMC4349753  PMID: 25745501
Antiretroviral treatment; Adverse drug reactions; Recurrent events
21.  Rates and Predictors of Non-Adherence to Antiretroviral Therapy among HIV-Positive Individuals in Kenya: Results from the Second Kenya AIDS Indicator Survey, 2012 
PLoS ONE  2016;11(12):e0167465.
Introduction
Understanding the levels and associated factors of non-adherence to antiretroviral therapy (ART) is crucial in designing interventions to improve adherence and health outcomes of ART. We assessed non-adherence to ART among HIV-infected persons reporting ART use in a nationally representative survey in Kenya.
Methods
The Kenya AIDS Indicator Survey 2012 was a population-based, household survey of persons aged 18 months-64 years conducted in 2012–2013. Self-reported information was collected on demographics, sexual behaviour, HIV status, and ART use. Blood was collected for HIV testing, and if HIV infected, CD4 and viral load testing. HIV-positive specimens were tested for the presence of antiretroviral (ARV) drugs using a qualitative ARV assay using liquid chromatography-tandem mass spectrometry. HIV-positive persons who reported receiving ART but did not have the ARV biomarker present were defined as being non-adherent to their ARV medication. We restricted our analysis to HIV-infected persons aged 15–64 years who reported receiving ART and had laboratory-confirmed results from ARV testing. Multivariate logistic regression was used to identify variables associated with non-adherence.
Results
A total of 648 (5.6%; CI 4.9–6.3) tested HIV-positive of whom 559 (86.3%) had sufficient volume of blood to be tested for ARV drugs. Of those, 271 (47.7%; CI 41.8–53.6) self-reported HIV-positive status during the interview and 186 (69.1%; CI 62.2–76.0) of those reported taking ART. The ARV biomarker was absent in 18 of 186 individuals (9.4%; CI 4.9–13.8) who thus were defined as being non-adherent to ART. Non-adherence was associated with being aged 15–29 years (AOR 8.39; CI 2.26–31.22, p = 0.002) compared to aged 30–64 years, rural residence (AOR 5.87; CI 1.39–25.61, p = 0.016) compared with urban residence and taking recreational drugs in the past 30 days (AOR 5.89; CI 1.30–26.70, p = 0.022).
Conclusion
Overall, less than 10% of Kenyans aged 15–64 years on ART were not adhering to their HIV medication, highlighting the success of the Kenyan national ART program. Our findings, however, point to the need for targeted interventions particularly for young persons, those in rural areas to improve adherence outcomes, as well as delivery of treatment programs that include psychosocial support as a preventative measure to minimize substance abuse and the risk of treatment failure.
doi:10.1371/journal.pone.0167465
PMCID: PMC5131960  PMID: 27907114
22.  Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals☆ 
Life sciences  2010;88(21-22):959-971.
Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV+ pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.
doi:10.1016/j.lfs.2010.09.012
PMCID: PMC3100475  PMID: 20932495
P-glycoprotein; Multidrug resistance-associated protein; Breast cancer resistance protein; Cytochrome P-450; Antiretrovirals agents; Protease inhibitors and drugs of abuse
23.  A pharmacovigilance study of adults on highly active antiretroviral therapy, South Africa: 2007 – 2011 
Background
Of the 1.6 million South African people infected with human immunodeficiency virus (HIV), approximately 970,000 (55%) have been initiated on HAART. Despite these numbers, very little has been published about the safety profile of antiretroviral (ARV) medicines in the country. This study was performed at the Medunsa National Pharmacovigilance Centre and aimed to describe the demographic characteristics of patients enrolled in the pharmacovigilance surveillance study; highly active antiretroviral therapy (HAART) initiation regimen patterns; reasons for regimen changes; and adverse effects of ARV medicines.
Methods
A cohort study of HIV-infected individuals aged 15 years or older who were on ARV medicines was conducted at four sentinel sites.
Results
After HAART initiation, with an average lapse of 17.8 months (range: 0 – 83.8 months), 2,815 patients were enrolled into the study. Results show that patients were observed for 1,606.2 person-years for pharmacy visits (collection of ARV medicines) and 817.1 person-years for clinical visits (consultation with the doctor). Females constituted 69.6% (1,958/2,815) of the study population. Almost all patients initiated HAART on first-line regimens (2,801/2,815). Some patients (6.7%, 190/2,815) dropped out of the study after HAART initiation. Reasons for regimen changes were not recorded for 2.5% (22/891) of the patients who changed regimens. The primary reason for regimen changes was drug-related toxicity (76.1%, 678/891), mostly evident in patients taking first-line regimens. Adverse effects experienced by patients were polyneuropathy (24.0%, 163/678); lipodystrophy (23.9%, 162/678); neuropathy (10.6%, 72/678); and suspected lactic acidosis (3.8%, 26/678).
Conclusion
The majority of prescribers complied with the HAART guidelines and initiated most patients on first-line regimens. However, adverse effects are evident in patients taking first-line regimens. We recommend that the Department of Health should introduce less toxic first-line ARV regimens. Future efforts will aim to initiate patients on HAART and enrol them into the study simultaneously to determine early risk profiles of ARV medicines.
PMCID: PMC3343667  PMID: 22593775
Pharmacovigilance; human immunodeficiency virus; antiretroviral medicines; surveillance
24.  What do mathematical models tell us about the emergence and spread of drug-resistant HIV? 
Current opinion in HIV and AIDS  2011;6(2):131-140.
Structured abstract
Purpose of review
To discuss recent HIV epidemic models examining the transmission of antiretroviral (ARV) drug resistance.
Recent findings
A relatively small number of recent transmission models have investigated ARV resistance in the context of therapeutic, combined ART (cART); ARV-vaginal microbicides (ARV-VMB); and oral pre-exposure prophylaxis (PrEP). Models of cART use have highlighted potential concerns about future resistance transmission, particularly in resource-constrained settings, and have emphasized the benefits of viral load monitoring in limiting resistance spread. PrEP models have concluded that inadvertent use by HIV-infected individuals could increase resistance prevalence, and that risk compensation by PrEP users could limit their beneficial effects on HIV transmission. ARV-VMB models have demonstrated that while resistance can reduce prophylactic effectiveness in preventing HIV acquisition of female ARV-VMB users, it may concomitantly benefit users' male partners if the resistant strains that female users acquire are less transmissible than wild-type strains. The models have examined the balance between these two factors at the population level.
Summary
Recent HIV transmission models have adopted a wide assortment of structures and assumptions to explore drug resistance in the context of different ARV interventions in various settings. There is a need for future work emphasizing the simultaneous effects of multiple ARV interventions, as well as the public health impact of resistance, not just its prevalence.
doi:10.1097/COH.0b013e328343ad03
PMCID: PMC3096989  PMID: 21505388
HIV; mathematical modeling; antiretroviral; resistance; pre-exposure prophylaxis (PrEP); microbicides
25.  Safety of Perinatal Exposure to Antiretroviral Medications: Developmental Outcomes in Infants 
Background
This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants.
Methods
HIV-exposed, uninfected infants (age 9-15 months) enrolled in SMARTT, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development—Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development, and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class), and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates.
Results
As of May 2010, 374 infants had valid Bayley-III evaluations. Median age at testing was 12.7 months; 49% male, 79% black, 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (PIs; 9% of PI-containing regimens also included non-nucleoside reverse transcriptase inhibitors [NNRTIs]), 5% to regimens containing NNRTIs (without PI), and 14% to regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs). Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen, or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (p=0.01).
Conclusions
These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study.
doi:10.1097/INF.0b013e318284129a
PMCID: PMC3723344  PMID: 23340561
HIV; ARV; infant; neurodevelopment; developmental assessment

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