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1.  Diabetic Mastopathy: A Case Report and Literature Review 
Case Reports in Oncology  2010;3(2):245-251.
Diabetic mastopathy is a rare fibroinflammatory breast disease characterized by lymphocytic lobulitis, ductitis, and perivasculitis with stromal fibrosis. This lesion often presents as a discretely palpable uni- or bilateral mass in long-standing type I diabetes and other autoimmune diseases. We report a case of insulin-dependent diabetic mastopathy, which presented clinically as an indeterminate breast lump suspicious for malignancy. The patient is a 36-year-old woman who had type 1 insulin-dependent diabetes mellitus. Mammography and ultrasonography raised a suspicion of malignancy, and an excisional biopsy was performed. A previous biopsy had shown no evidence of malignancy. Histopathological examination now showed dense keloid-like stromal fibrosis with epithelioid-like and spindly myofibroblasts and a characteristic lymphocytic infiltration around blood vessels in and around lobules and ducts, features consistent with diabetic mastopathy. The literature is briefly reviewed.
PMCID: PMC2920008  PMID: 20740205
Diabetic mastopathy; Insulin-dependent; Breast cancer; Pseudomalignancy
2.  Autoantibody with Cross-Reactivity between Insulin and Ductal Cells May Cause Diabetic Mastopathy: A Case Study 
Case Reports in Medicine  2012;2012:569040.
Lymphocytic mastopathy or diabetic mastopathy is a benign breast disease characterized by dense fibrosis, lobular atrophy, and aggregates of lymphocytes in a periductal and perilobular distribution. The condition usually affects women with a long history of diabetes mellitus (DM) and also those with autoimmune disorders. While the pathogenesis is unknown, a particular type of class II human leukocyte antigen has been associated with this disease. Herein, we report a case of diabetic mastopathy which clinically and radiologically mimicked primary breast neoplasms. The patient was a 74-year-old woman with a 31-year history of DM type II who presented with multiple firm lumps in bilateral breasts. Findings from mammography, ultrasonography, and magnetic resonance imaging of the breasts revealed an abnormal appearance which suspiciously resembled malignancy. An aspiration cytology specimen showed atypical accumulation of lymphoid cells, leading us to suspect lymphoma. Histology of an excisional biopsy showed the characteristic appearance of lymphocytic mastopathy, which predominantly consisted of B-lymphocytes. Autoantibodies in her serum reacted positively against her ductal epithelium as well as other diabetic and nondiabetic breast ductal cells. An antigen absorption test with insulin revealed attenuating intensity according to insulin concentration. These anti-insulin antibodies produced in the DM patient may cause ductitis because of antigen cross-reactivity.
PMCID: PMC3346992  PMID: 22577391
3.  Leptin in Relation to the Lipodystrophy-Associated Metabolic Syndrome 
Diabetes & Metabolism Journal  2012;36(3):181-189.
Leptin, an adipocyte-secreted hormone, regulates energy homeostasis as well as reproductive, neuroendocrine, immune and metabolic functions. Subjects with decreased amounts of fat in their adipose tissue, i.e., lipoatrophy, have low leptin levels. In the context of open-label, uncontrolled studies leptin administration, in physiological replacement doses, has been shown to have metabolically salutary effects in the rare patients with the syndrome of congenital lipodystrophy accompanied by leptin deficiency. Much more patients with lipodystrophy suffer from lipodystrophy and the metabolic syndrome associated with the use of highly active antiretroviral therapy. In this so called highly active antiretroviral therapy (HAART)-associated lipodystrophy and metabolic syndrome, patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Leptin administration has been shown to decrease central fat mass and to improve fasting insulin/glucose levels and insulin sensitivity in human immunodeficiency virus-infected hypoleptinemic patients with HAART induced lipodystrophy and the metabolic syndrome. By contrast, the results of leptin treatment in leptin replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. In this review, we present the emerging clinical applications and potential therapeutic uses of leptin in humans with lipodystrophy and the metabolic syndrome.
PMCID: PMC3380121  PMID: 22737657
Antiretroviral therapy, highly active; Glucose metabolism; HIV; Leptin; Lipodystrophy
4.  Diabetic Mastopathy as a Radiographically Occult Palpable Breast Mass 
Case Reports in Medicine  2011;2011:162350.
Diabetic mastopathy is an uncommon, benign disease of the breast that can occur in women with diabetes and clinically mimic breast cancer. We describe a patient with long-standing type 1 diabetes who presented with a palpable breast mass with negative imaging findings on mammography, ultrasonography, and breast MRI. Surgical biopsy and histopathology confirmed diabetic mastopathy. We use this case to highlight the recognition, radiographic features, pathology, and management of this benign breast condition and emphasize that, in diabetic patients, the differential diagnosis of a new breast mass should include diabetic mastopathy.
PMCID: PMC3216295  PMID: 22110508
5.  A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes 
PLoS Medicine  2011;8(3):e1000422.
Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.
Methods and Findings
A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49–1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21–0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65–1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53–1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.
Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.
Trial registration
ClinicalTrials gov NCT00273780
Please see later in the article for the Editors' Summary
Editors' Summary
Adherence to HIV treatment programs in poor countries has long been cited as an important public health concern, especially as poor adherence can lead to drug resistance and inadequate treatment of HIV. However, two factors have recently cast doubt on the poor adherence problem: (1) recent studies have shown that adherence is high in African HIV treatment programs and often better than in Western HIV clinics. For example, in a meta-analysis of 27 cohorts from 12 African countries, adequate adherence was noted in 77% of subjects compared to only 55% among 31 North America cohorts; (2) choice of antiretroviral regimens may impact on the development of antiretroviral resistance. In poor countries, most antiretroviral regimens contain non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine or efavirenz, which remain in the patient's circulation for weeks after single-dose administration. This situation means that such patients may not experience antiretroviral resistance unless they drop below 80% adherence—contrary to the more stringent 95% plus adherence levels needed to prevent resistance in regimens based on unboosted protease inhibitors—ultimately, off-setting some treatment lapses in resource-limited settings where NNRTI-based regimens are widely used.
Why Was This Study Done?
Given that adherence may not be as crucial an issue as previously thought, antiretroviral treatment programs in sub-Saharan Africa may be spending scarce resources to promote adherence to the detriment of some potentially more effective elements of HIV treatment and management programs. Although many treatment programs currently include adherence interventions, there is limited quality evidence that any of these methods improve long-term adherence to HIV treatment. Therefore, it is necessary to identify adherence interventions that are inexpensive and proven to be effective in resource-limited settings. As adherence counseling is already widely implemented in African HIV treatment programs and inexpensive alarm devices are thought to also improve compliance, the researchers compared the impact of adherence counseling and the use of an alarm device on adherence and biological outcomes in patients enrolled in HIV programs in rural Kenya.
What Did the Researchers Do and Find?
The researchers enrolled 400 eligible patients (newly diagnosed with HIV, never before taken antiretroviral therapy, aged over 18 years) to four arms: (1) adherence counseling alone; (2) alarm device alone; (3) both adherence counseling and alarm device together; and (4) a control group that received neither adherence counseling nor alarm device. The patients had blood taken to record baseline CD4 count and HIV-1 RNA and after starting HIV treatment, returned to the study clinic every month with their pill bottles for the study pharmacist to count and recorded the number of pills remaining in the bottle, and to receive another prescription. Patients were followed up for 18 months and had their CD4 count and HIV-1 RNA measured at 6, 12, and 18 months.
Patients receiving adherence counseling were 29% less likely to experience poor adherence compared to those who received no counseling. Furthermore, those receiving intensive early adherence counseling were 59% less likely to experience viral failure. However, there was no significant difference in mortality or significant differences in CD4 counts at 18 months follow-up between those who received counseling and those who did not. There were no significant differences in adherence, time to viral failure, mortality, or CD4 counts in patients who received alarm devices compared to those who did not.
What Do These Findings Mean?
The results of this study suggest that intensive adherence counseling around the time of HIV treatment initiation significantly reduces poor adherence and virologic treatment failure, while using an alarm device has no effect. Therefore, investment in careful counseling based on individual needs at the onset of HIV treatment initiation, appears to have sustained benefit, possibly through strengthening the relationship between the health care provider and patient through communication, education, and trust. Interactive adherence counseling supports the bond between the clinic and the patient and may result in fewer patients needing to switch to expensive second-line medications and, possibly, may help to decrease the spread of resistant HIV. These findings define an adherence counseling protocol that is effective and are highly relevant to other HIV clinics caring for large numbers of patients in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at
UNAIDS provides information about HIV treatment strategies
The American Public Health Association has information about adherence to HIV treatment regimens
The US Department of Health and Human Services has information for patients about adherence to HIV treatment
The World Health Organization provides information about HIV treatment pharmacovigilance
PMCID: PMC3046986  PMID: 21390262
6.  Accessory nipple reconstruction following a central quadrantectomy: a case report 
Cases Journal  2009;2:32.
nipple dichotomy (or intra-areolar polythelia) is a rare congenital malformation in which one or more supernumerary nipples are located within the same areola.
A case of a woman undergoing a central quadrantectomy with a contralateral supernumerary nipple used for reconstruction is reported. No other report in the Literature, according to our search, has focused on reconstructive use of an accessory nipple after breast conserving surgery.
Case presentation
the patient is a 73 year-old Caucasian woman, who two years earlier underwent a lower-outer left Quadrantectomy plus axillary sampling and radiation therapy for a 2,2 cm lobular carcinoma with no lymph node involvement.
A routine follow-up assessment showed an important fibrotic change on the operated breast, just across the infra-mammary fold; at a breast Magnetic Resonance Imaging, a 1,5 cm area in retroareolar position, suspicious for local recurrence, was evident.
An open biopsy was therefore performed, under local anaesthesia, including the nipple-areolar complex to realize a central Quadrantectomy with a Grisotti procedure; a congenital dichotomic nipple in the contralateral breast was then used to repair the defect through a "nipple-sharing" technique. The final histological examination reported a fibrotic mastopathy without atypias.
in this case, the "nipple-sharing" technique has allowed in the same time the correction of a rare congenital defect and provided the surgeon with a supernumerary nipple to be used in the immediate reconstruction after breast conserving surgery.
PMCID: PMC2639561  PMID: 19133154
7.  Warfarin-induced skin necrosis in HIV-1-infected patients with tuberculosis and venous thrombosis 
At the turn of the century, only 300 cases of warfarin-induced skin necrosis (WISN) had been reported. WISN is a rare but potentially fatal complication of warfarin therapy. There are no published reports of WISN occurring in patients with HIV-1 infection or tuberculosis (TB).
We retrospectively reviewed cases of WISN presenting from April 2005 to July 2008 at a referral hospital in Cape Town, South Africa.
Six cases of WISN occurred in 973 patients receiving warfarin therapy for venous thrombosis (0.62%, 95% CI 0.25 - 1.37%). All 6 cases occurred in HIV-1-infected women (median age 30 years, range 27 - 42) with microbiologically confirmed TB and venous thrombosis. All were profoundly immunosuppressed (median CD4+ count at TB diagnosis 49 cells/μl, interquartile range 23 - 170). Of the 3 patients receiving combination antiretroviral therapy, 2 had TB-IRIS (immune reconstitution inflammatory syndrome). The median interval from initiation of antituberculosis treatment to venous thrombosis was 37 days (range 0 - 150). The median duration of parallel heparin and warfarin therapy was 2 days (range 1 - 6). WISN manifested 6 days (range 4 - 8) after initiation of warfarin therapy. The international normalised ratio (INR) at WISN onset was supra-therapeutic, median 5.6 (range 3.8 - 6.6). Sites of WISN included breasts, buttocks and thighs. Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 - 37 days after WISN onset. In 4 patients, the median interval from WISN onset to death was 43 days (range 25 - 45). One of the 2 patients who survived underwent bilateral mastectomies and extensive skin grafting at a specialist centre.
This is one of the largest case series of WISN. We report a novel clinical entity: WISN in HIV-1 infected patients with TB and venous thrombosis. The occurrence of 6 WISN cases in a 40-month period may be attributed to (i) hypercoagulability, secondary to HIV-1 and TB; (ii) short concurrent heparin and warfarin therapy; and (iii) high loading doses of warfarin. Active prevention and appropriate management of WISN are likely to improve the dire morbidity and mortality of this unusual condition.
PMCID: PMC3506217  PMID: 20529438
8.  Comparison of Serum Lipid Profile in HIV Positive Patients on ART with ART Naïve Patients 
Introduction: The widespread use of effective highly active antiretroviral therapy (HAART) in HIV patients has coincided with increasing reports of complications like HIV-associated lipodystrophy syndrome and the metabolic alterations, affecting the lipid and glucose metabolism. Evidences in support of lipodystrophy and dyslipidaemia associated with First- line HAART in our area is scarce. The aim of the present study was 1) to study and compare Lipid profile in HIV positive patients on ART with that of freshly diagnosed HIV positive patients who were yet to be started on ART. 2) To assess lipodystrophy syndrome in patients on ART.
Materials and Methods: Hundred newly diagnosed HIV positive patients who were yet to be started on ART were taken as controls (ART-Naïve).Hundred randomly selected HIV+ patients who were already on First-line ART regimen (Stavudine/Zudovudine + Lamivudine + Nevirapine) for more than 12 months were taken as cases (ART). This study was conducted for a period of 12 months at the VIMS ART centre, Bellary, Karnataka, India.
Results: There was a significant increase (p<0.001) in serum Total Cholesterol, LDL-C, TG, VLDL, Non-HDL -C & TC/HDL-C ratio in ART patients compared to ART-naïve patients. Of the 100 ART patients 23 had lipodystrophy syndrome (buffalo hump, abnormal fat deposition around neck & back, buccal fat resorption, increase in abdominal fat).
Conclusion: To conclude, it is evident from our study that there is increase in lipid profile (except HDL) in ART patients compared to ART Naïve group and 23 ART patients showed lipodystrophy syndrome. Hence it appears reasonable to measure fasting lipid levels before and 3-6 months after antiretroviral therapy is initiated or when ART regimen is changed.
PMCID: PMC4253153  PMID: 25478335
First line HAART regimen; Lipodystrophy syndrome; Lipid profile
9.  Impact of Antiretroviral Therapy on Incidence of Pregnancy among HIV-Infected Women in Sub-Saharan Africa: A Cohort Study 
PLoS Medicine  2010;7(2):e1000229.
A multicountry cohort study in sub-Saharan Africa by Landon Myer and colleagues reveals higher pregnancy rates in HIV-infected women on antiretroviral therapy (ART).
With the rapid expansion of antiretroviral therapy (ART) services in sub-Saharan Africa there is growing recognition of the importance of fertility and childbearing among HIV-infected women. However there are few data on whether ART initiation influences pregnancy rates.
Methods and Findings
We analyzed data from the Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative, a multicountry HIV care and treatment program for women, children, and families. From 11 programs in seven African countries, women were enrolled into care regardless of HIV disease stage and followed at regular intervals; ART was initiated according to national guidelines on the basis of immunological and/or clinical criteria. Standardized forms were used to collect sociodemographic and clinical data, including incident pregnancies. Overall 589 incident pregnancies were observed among the 4,531 women included in this analysis (pregnancy incidence, 7.8/100 person-years [PY]). The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (adjusted hazard ratio, 1.74; 95% confidence interval, 1.19–2.54). Other factors independently associated with increased risk of incident pregnancy included younger age, lower educational attainment, being married or cohabiting, having a male partner enrolled into the program, failure to use nonbarrier contraception, and higher CD4 cell counts.
ART use is associated with significantly higher pregnancy rates among HIV-infected women in sub-Saharan Africa. While the possible behavioral or biomedical mechanisms that may underlie this association require further investigation, these data highlight the importance of pregnancy planning and management as a critical but neglected component of HIV care and treatment services.
Please see later in the article for the Editors' Summary
Editors' Summary
Human immunodeficiency virus (HIV) causes Acquired Immunodeficiency Syndrome (AIDS), which is a major global cause of disease and death. More than 33 million people around the world are infected with HIV, with nearly 5,500 dying daily from HIV and AIDS-related complications. HIV/AIDS is especially problematic in sub-Saharan Africa, where it is the leading cause of death. There is no cure for HIV/AIDS, but medicines known as “antiretroviral therapy” (ART) can prolong life and reduce complications in patients infected with HIV. 97% of patients with HIV/AIDS live in low- and middle-income countries. According to the World Health Organization, nearly 10 million of these patients need ART. As patients' access to treatment is often hindered by the high cost and low availability of ART, global health efforts have focused on promoting ART use in resource-limited nations. Such efforts also increase awareness of how HIV is spread (contact with blood or semen, in sexual intercourse, sharing needles, or from mother to child during childbirth). ART reduces, but does not remove, the chance of a mother's passing HIV to her child during birth.
Why Was This Study Done?
By the end of 2007, 3 million HIV-infected patients in poor countries were receiving ART. Many of those treated with ART are young women of child-bearing age. Childbirth is an important means of spreading HIV in sub-Saharan Africa, where 60% of all HIV patients are women. This study questions whether the improved health and life expectancy that results from treatment with ART affects pregnancy rates of HIV-infected patients. The study explores this question in seven African countries, by examining the rates of pregnancy in HIV-infected women before and after they started ART.
What Did the Researchers Do and Find?
The authors looked at the records of 4,531 HIV-infected women enrolled in the Mother-to-Child-Transmission-Plus (MTCT-Plus) Initiative in seven African countries. MTCT -Plus, begun in 2002, is a family-centered treatment program that offers regular checkups, blood tests, counseling, and ART treatment (if appropriate) to women and their families. At each checkup, women's CD4+ cell counts and World Health Organization guidelines were used to determine their eligibility for starting ART. Over a 4-year period, nearly a third of the women starting ART experienced a pregnancy: 244 pregnancies occurred in the “pre-ART” group (women not receiving ART) compared to 345 pregnancies in the “on-ART” group (women receiving ART). The chance of pregnancy increased over time in the on-ART group to almost 80% greater than the pre-ART group, while remaining relatively low and constant in the pre-ART group. The authors noted that, as expected, other factors also increased the chances of pregnancy, including younger age, lower educational status, and use of nonbarrier contraception such as injectable hormones.
What Do These Findings Mean?
This study suggests that starting ART is associated with higher pregnancy rates in sub-Saharan Africa, nearly doubling the chances of a woman becoming pregnant. The reasons for this link are unclear. One possible explanation is behavioral: women receiving ART may feel more motivated to have children as their health and quality of life improve. However, the study did not examine how pregnancy desires and sexual activity of women changed while on ART, and cannot discern why ART is linked to increased pregnancy. By using pregnancy data gathered from patient questionnaires rather than laboratory tests, the study is limited by the possibility of inaccurate patient reporting. Understanding how pregnancy rates vary in HIV-infected women receiving ART helps support the formation of responsive, effective HIV programs. Female HIV patients of child-bearing age, who form the majority of patients receiving ART in sub-Saharan Africa, would benefit from programs that combine starting HIV treatment with ART with education and contraception counseling and pregnancy-related care.
Additional Information
Please access these Web sites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of articles and other sources of information about the primary care of adolescents with HIV
A UNAIDS 2008 report is available on the global AIDS epidemic
The International Planned Parenthood Foundation provides information on sexual and reproductive health and HIV
The International Center for AIDS Care and Treatment Programs at the Columbia University Mailman School of Public health provides information to assist HIV care and treatment programs in resource-limited settings
PMCID: PMC2817715  PMID: 20161723
10.  Crusted scabies-associated immune reconstitution inflammatory syndrome 
BMC Infectious Diseases  2012;12:323.
Despite the widely accepted association between crusted scabies and human immunodeficiency virus (HIV)-infection, crusted scabies has not been included in the spectrum of infections associated with immune reconstitution inflammatory syndrome in HIV-infected patients initiating antiretroviral therapy.
Case presentation
We report a case of a 28-year-old Mexican individual with late HIV-infection, who had no apparent skin lesions but soon after initiation of antiretroviral therapy, he developed an aggressive form of crusted scabies with rapid progression of lesions. Severe infestation by Sarcoptes scabiei was confirmed by microscopic examination of the scale and skin biopsy. Due to the atypical presentation of scabies in a patient responding to antiretroviral therapy, preceded by no apparent skin lesions at initiation of antiretroviral therapy, the episode was interpreted for the first time as “unmasking crusted scabies-associated immune reconstitution inflammatory syndrome”.
This case illustrates that when crusted scabies is observed in HIV-infected patients responding to antiretroviral therapy, it might as well be considered as a possible manifestation of immune reconstitution inflammatory syndrome. Patient context should be considered for adequate diagnosis and treatment of conditions exacerbated by antiretroviral therapy-induced immune reconstitution.
PMCID: PMC3573932  PMID: 23181485
Crusted scabies; IRIS; HIV; AIDS; ART
11.  A Metabolic Syndrome Case Presenting with Lymphocytic Mastitis 
Breast Care  2012;7(6):493-495.
Lymphocytic mastitis is a disease of premenopausal women, and its association with type 1 diabetes mellitus is the basis for its alternative name ‘diabetic mastopathy’. It is a benign condition but must be considered in the differential diagnosis of breast cancer, especially in diabetic patients.
Case Report
We present the case of an overweight 50-year-old dyslipidemic woman with metabolic syndrome presenting with lymphocytic mastitis.
Although lymphocytic mastitis is usually regarded as an autoimmune disease seen mostly in diabetic patients, it may also be seen in nondiabetic patients with metabolic syndrome who do not have an autoimmune disease.
PMCID: PMC3971797  PMID: 24715834
Lymphocytic mastitis; Metabolic syndrome
12.  Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART 
PLoS Medicine  2006;3(9):e356.
The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART.
Methods and Findings
Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance.
We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period.
Emergence of resistance to both non-nucleoside reverse transcriptase inhibitors and protease inhibitors was associated with a higher risk of subsequent death, but the risk was greater in patients with NNRTI-resistant HIV.
Editors' Summary
In the 1980s, infection with the human immunodeficiency virus (HIV) was effectively a death sentence. HIV causes AIDS (acquired immunodeficiency syndrome) by replicating inside immune system cells and destroying them, which leaves infected individuals unable to fight off other viruses and bacteria. The first antiretroviral drugs were developed quickly, but it soon became clear that single antiretrovirals only transiently suppress HIV infection. HIV mutates (accumulates random changes to its genetic material) very rapidly and, although most of these changes (or mutations) are bad for the virus, by chance some make it drug resistant. Highly active antiretroviral therapy (HAART), which was introduced in the mid-1990s, combines three or four antiretroviral drugs that act at different stages of the viral life cycle. For example, they inhibit the reverse transcriptase that the virus uses to replicate its genetic material, or the protease that is necessary to assemble new viruses. With HAART, the replication of any virus that develops resistance to one drug is inhibited by the other drugs in the mix. As a consequence, for many individuals with access to HAART, AIDS has become a chronic rather than a fatal disease. However, being on HAART requires patients to take several pills a day at specific times. In addition, the drugs in the HAART regimens often have side effects.
Why Was This Study Done?
Drug resistance still develops even with HAART, often because patients don't stick to the complicated regimens. The detection of resistance to one drug is usually the prompt to change a patient's drug regimen to head off possible treatment failure. Although most patients treated with HAART live for many years, some still die from AIDS. We don't know much about how the emergence of drug-resistance mutations affects mortality in patients who are starting antiretroviral therapy for the first time. In this study, the researchers looked at how the emergence of drug resistance affected survival in a group of HIV/AIDS patients in British Columbia, Canada. Here, everyone with HIV/AIDS has access to free medical attention, HAART, and laboratory monitoring, and full details of all HAART recipients are entered into a central reporting system.
What Did the Researchers Do and Find?
The researchers enrolled people who started antiretroviral therapy for the first time between August 1996 and September 1999 into the HAART Observational Medical Evaluation and Research (HOMER) cohort. They then excluded anyone who was infected with already drug-resistant HIV strains (based on the presence of drug-resistance mutations in viruses isolated from the patients) at the start of therapy. The remaining 1,138 patients were followed for an average of five years. All the patients received either two nucleoside reverse transcriptase inhibitors and a protease inhibitor, or two nucleoside and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Nearly a fifth of the study participants died during the follow-up period. Most of these patients actually had drug-sensitive viruses, possibly because they had neglected taking their drugs to such an extent that there had been insufficient drug exposure to select for drug-resistant viruses. In a quarter of the patients, however, HIV strains resistant to one or more antiretroviral drugs emerged during the study (again judged by looking for mutations). Detailed statistical analyses indicated that the emergence of any drug resistance nearly doubled the risk of patients dying, and that people carrying viruses resistant to NNRTIs were three times as likely to die as those without resistance to this class of antiretroviral drug.
What Do These Findings Mean?
These results provide new information about the emergence of drug-resistant HIV during HAART and possible effects on the long-term survival of patients. In particular, they suggest that clinicians should watch carefully for the emergence of resistance to NNRTIs in their patients. Because this type of resistance is often due to poor adherence to drug regimens, these results also suggest that increased efforts should be made to ensure that patients comply with the prescribed HAART regimens, especially those whose antiretroviral therapy includes NNRTIs. As with all studies in which a group of individuals who share a common characteristic are studied over time, it is possible that some other, unmeasured difference between the patients who died and those who didn't—rather than emerging drug resistance—is responsible for the observed differences in survival. Additional studies are needed to confirm the findings here, and to investigate whether specific subpopulations of patients are at particular risk of developing drug resistance and/or dying during HAART.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Institute of Allergy and Infectious Diseases fact sheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS, including details of approved drugs for the treatment of HIV infection
US Centers for Disease Control and Prevention information on HIV/AIDS
Aidsmap, information on HIV and AIDS provided by the charity NAM, which includes details on antiretroviral drugs
PMCID: PMC1569883  PMID: 16984218
13.  Barriers to Provider-Initiated Testing and Counselling for Children in a High HIV Prevalence Setting: A Mixed Methods Study 
PLoS Medicine  2014;11(5):e1001649.
Rashida Ferrand and colleagues combine quantitative and qualitative methods to investigate HIV prevalence among older children receiving primary care in Harare, Zimbabwe, and reasons why providers did not pursue testing.
Please see later in the article for the Editors' Summary
There is a substantial burden of HIV infection among older children in sub-Saharan Africa, the majority of whom are diagnosed after presentation with advanced disease. We investigated the provision and uptake of provider-initiated HIV testing and counselling (PITC) among children in primary health care facilities, and explored health care worker (HCW) perspectives on providing HIV testing to children.
Methods and Findings
Children aged 6 to 15 y attending six primary care clinics in Harare, Zimbabwe, were offered PITC, with guardian consent and child assent. The reasons why testing did not occur in eligible children were recorded, and factors associated with HCWs offering and children/guardians refusing HIV testing were investigated using multivariable logistic regression. Semi-structured interviews were conducted with clinic nurses and counsellors to explore these factors. Among 2,831 eligible children, 2,151 (76%) were offered PITC, of whom 1,534 (54.2%) consented to HIV testing. The main reasons HCWs gave for not offering PITC were the perceived unsuitability of the accompanying guardian to provide consent for HIV testing on behalf of the child and lack of availability of staff or HIV testing kits. Children who were asymptomatic, older, or attending with a male or a younger guardian had significantly lower odds of being offered HIV testing. Male guardians were less likely to consent to their child being tested. 82 (5.3%) children tested HIV-positive, with 95% linking to care. Of the 940 guardians who tested with the child, 186 (19.8%) were HIV-positive.
The HIV prevalence among children tested was high, highlighting the need for PITC. For PITC to be successfully implemented, clear legislation about consent and guardianship needs to be developed, and structural issues addressed. HCWs require training on counselling children and guardians, particularly male guardians, who are less likely to engage with health care services. Increased awareness of the risk of HIV infection in asymptomatic older children is needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Over 3 million children globally are estimated to be living with HIV (the virus that causes AIDS). While HIV infection is most commonly spread through unprotected sex with an infected person, most HIV infections among children are the result of mother-to-child HIV transmission during pregnancy, delivery, or breastfeeding. Mother-to-child transmission can be prevented by administering antiretroviral therapy to mothers with HIV during pregnancy, delivery, and breast feeding, and to their newborn babies. According to a report by the Joint United Nations Programme on HIV/AIDS published in 2012, 92% of pregnant women with HIV were living in sub-Saharan Africa and just under 60% were receiving antiretroviral therapy. Consequently, sub-Saharan Africa is the region where most children infected with HIV live.
Why Was This Study Done?
If an opportunity to prevent mother-to-child transmission around the time of birth is missed, diagnosis of HIV infection in a child or adolescent is likely to depend on HIV testing in health care facilities. Health care provider–initiated HIV testing and counselling (PITC) for children is important in areas where HIV infection is common because earlier diagnosis allows children to benefit from care that can prevent the development of advanced HIV disease. Even if a child or adolescent appears to be in good health, access to care and antiretroviral therapy provides a health benefit to the individual over the long term. The administration of HIV testing (and counselling) to children relies not only on health care workers (HCWs) offering HIV testing but also on parents or guardians consenting for a child to be tested. However, more than 30% of children in countries with severe HIV epidemics are AIDS orphans, and economic conditions in these countries cause many adults to migrate for work, leaving children under the care of extended families. This study aimed to investigate the reasons for acceptance and rejection of PITC in primary health care settings in Harare, Zimbabwe. By exploring HCW perspectives on providing HIV testing to children and adolescents, the study also sought to gain insight into factors that could be hindering implementation of testing procedures.
What Did the Researchers Do and Find?
The researchers identified all children aged 6 to 15 years old at six primary care clinics in Harare, who were offered HIV testing as part of routine care between 22 January and 31 May 2013. Study fieldworkers collected data on numbers of child attendances, numbers offered testing, numbers who underwent HIV testing, and reasons why HIV testing did not occur. During the study 2,831 children attending the health clinics were eligible for PITC, and just over half (1,534, 54.2%) underwent HIV testing. Eighty-two children tested HIV-positive, and nearly all of them received counselling, medication, and follow-up care. HCWs offered the test to around 75% of those eligible. The most frequent explanation given by HCWs for a diagnostic test not being offered was that the child was accompanied by a guardian not appropriate for providing consent (401 occasions, 59%); Other reasons given were a lack of available counsellors or test kits and counsellors refusing to conduct the test. The likelihood of being offered the test was lower for children not exhibiting symptoms (such as persistent skin problems), older children, or those attending with a male or a younger guardian. In addition, over 100 guardians or parents provided consent but left before the child could be tested.
The researchers also conducted semi-structured interviews with 12 clinic nurses and counsellors (two from each clinic) to explore challenges to implementation of PITC. The researchers recorded the factors associated with testing not taking place, either when offered to eligible children or when HCWs declined to offer the test. The interviewees identified the frequent absence or unavailability of parents or legal guardians as an obstacle, and showed uncertainty or misconceptions around whether testing of the guardian was mandatory (versus recommended) and whether specifically a parent (if one was living) must provide consent. The interviews also revealed HCW concerns about the availability of adequate counselling and child services, and fears that a child might experience maltreatment if he or she tested positive. HCWs also noted long waiting times and test kits being out of stock as practical hindrances to testing.
What Do These Findings Mean?
Prevalence of HIV was high among the children tested, validating the need for PITC in sub-Saharan health care settings. Although 76% of eligible attendees were offered testing, the authors note that this is likely higher than in routine settings because the researchers were actively recording reasons for not offering testing and counselling, which may have encouraged heath care staff to offer PITC more often than usual. The researchers outline strategies that may improve PITC rates and testing acceptance for Zimbabwe and other sub-Saharan settings. These strategies include developing clear laws and guidance concerning guardianship and proxy consent when testing older children for HIV, training HCWs around these policies, strengthening legislation to address discrimination, and increasing public awareness about HIV infection in older children.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Davies and Kalk
The Joint United Nations Programme on HIV/AIDS publishes an annual report on the global AIDS epidemic, which provides information on progress towards eliminating new HIV infections
The World Health Organization has more information on mother-to-child transmission of HIV
The World Health Organization's website also has information about treatment for children living with HIV
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
PMCID: PMC4035250  PMID: 24866209
14.  Human immunodeficiency virus infection: personal experience in changes in head and neck manifestations due to recent antiretroviral therapies 
Both the incidence and prevalence of human immunodeficiency virus infection are increasing in the world. Diseases of ENT districts are more frequent in human immunodeficiency virus-infected patients and involve all the otolaryngological sites. The otorhinolaryngological manifestations in association with HIV infection are mainly atypical, so common in the clinical practice, really aspecific and very frequent in ENT daily routine (such as sinusitis, otitis, etc.) and, therefore, immunodeficiency may not be suspected. In other cases, ENT evidence is more peculiar or unusual, such as opportunistic infections, rare neoplasm and tumours with an unusual course, giving a very high suspect of a human immunodeficiency virus-related infection. The most frequent malignant neoplasm is Kaposi’s Sarcoma which is extremely rare in non-human immunodeficiency virus-infected subjects; the second most frequent is non-Hodgkin’s lymphoma with 50% in extranodal sites (oral and maxillary sinus). Following a review of the literature, modifications caused by current antiretroviral treatment on head and neck manifestations of human immunodeficiency virus infection have been evaluated. Highly active antiretroviral therapy is a new therapeutic strategy, based on poly-chemo-therapeutic schemes, providing simultaneously two or more anti-retroviral drugs. We have used highly active antiretroviral therapy in human immunodeficiency virus infection since 1997, substituting previous mono-chemotherapy based on Zidovudine or Didanosine alone. Highly active antiretroviral therapy is extremely efficient in reducing the viral load of human immunodeficiency virus and increasing CD4+ T-lymphocyte count. These biological effects are associated with an improvement in immune functions. To evaluate the effects of highly active antiretroviral therapy on otorhinolaryngological manifestations in human immunodeficiency virus infection, we performed a retrospective study on 470 adults, observed over 14 years (1989-2002) and constantly receiving the same treatment, with follow-up from 7 to 80 months. A total of 250 subjects underwent mono-antiretroviral chemotherapy (1989-1996), while 220 underwent highly active antiretroviral therapy (1997-2002). The results of the retrospective study showed that highly active antiretroviral therapy has greatly improved the control of the immune-deficiency (increasing the range of CD4+), reducing the number of otorhinolaryngological manifestations (also tumours). On the other hand, 2 patients presented sudden unilateral hearing loss following treatment: toxicity due to association of new drugs cannot be excluded.
PMCID: PMC2639849  PMID: 16080313
HIV; AIDS; ENT manifestations; Antiretroviral therapy
15.  Body image in women with HIV: a cross-sectional evaluation 
HIV lipodystrophy syndrome is a recognized complication of potent antiretroviral therapy and is characterized by often dramatic changes in various body fat stores, both central and peripheral. Given prior findings of heightened body image dysphoria among HIV-infected men with lipodystrophy as compared to HIV-infected men without lipodystrophy, we sought to determine body image among HIV-infected and HIV-negative women and to determine the relationship of HIV and lipodystrophy with body image. Our a priori hypothesis was that women with HIV and lipodystrophy would have significantly poorer body image as compared to women without HIV and to women with HIV without lipodystrophy.
116 women responded to two previously validated self-report instruments (Body Image Quality of Life Index (BIQLI) and the Situational Inventory of Body-Image Dysphoria – Short Form (SIBID-S)) on body image. 62 (53% subjects) HIV-infected women were recruited at the university-based HIV clinic. 54 (47% subjects) HIV-negative female controls were recruited from another study evaluating bone density in otherwise healthy controls. 96% identified their sexual orientation as women having sex with men. Among the HIV-infected group, 36 reported the presence of lipodystrophic characteristics and 26 reported no lipodystrophic changes. Agreement regarding the presence of lipodystrophy between physician and subject was 0.67 as measured by the kappa coefficient of agreement. Compared to HIV-negative women, HIV-positive women demonstrated poor body image as measured by BIQLI (p = 0.0009). Compared with HIV-infected women who denied lipodystrophy, HIV-infected women with self-reported lipodystrophy demonstrated poor body image as measured by BIQLI (p = 0.02) and SIBID-S scales (p = 0.001).
We demonstrate that HIV and lipodystrophy status among women is associated with poor body image. Universal efforts should be made in the HIV medical community to recognize body image issues particularly among persons affected by lipodystrophy so that appropriate intervention and support may be provided.
PMCID: PMC1553466  PMID: 16824226
16.  HIV: prevention of mother-to-child transmission  
Clinical Evidence  2011;2011:0909.
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without antiretroviral treatment, the risk of HIV transmission from infected mothers to their children is 15% to 30% during gestation or labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads, advanced disease, or both, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood. Mixed feeding practices (breast milk plus other liquids or solids) and prolonged breastfeeding are also associated with increased risk of mother-to-child transmission of HIV.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother-to-child transmission of HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, micronutrient supplements, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breastfeeding is the norm. Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15% to 30% during pregnancy and labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding.HIV-2 is rarely transmitted from mother to child.Transmission is more likely in mothers with high viral loads, advanced HIV disease, or both.Without antiretroviral treatment (ART), 15% to 35% of vertically infected infants die within the first year of life.The long-term treatment of children with ART is complicated by multiple concerns regarding the complications associated with life-long treatment, including adverse effects of antiretroviral drugs, difficulties of adherence across the developmental trajectory of childhood and adolescence, and the development of resistance.From a paediatric perspective, successful prevention of MTCT and HIV-free survival for infants remain the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, to the baby immediately after birth, or to the mother and baby reduce the risk of intrauterine and intrapartum MTCT of HIV-1 and when given to the infant after birth and to the mother or infant during breastfeeding reduce the risk of postpartum MTCT of HIV-1.
Reductions in MTCT are possible using multidrug ART regimens. Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1% to 2%. Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. There is evidence that short courses of antiretroviral drugs have confirmed efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.The development of viral resistance in mothers and infants after single-dose nevirapine and other short-course regimens that include single-dose nevirapine is of concern. An additional short-course of antiretrovirals with a different regimen during labour and early postpartum, and the use of HAART, may decrease the risk of viral resistance in mothers, and in infants who become HIV-infected despite prophylaxis.World Health Organization guidelines recommend starting prophylaxis with antiretroviral drugs from as early as 14 weeks' gestation, or as soon as possible if women present late in pregnancy, in labour, or at delivery.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission). The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin seems no more effective than immunoglobulin without HIV antibody at reducing HIV-1 MTCT risk.
Vaginal microbicides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that supplementation with vitamin A reduces the risk of HIV-1 MTCT, and there is concern that postnatal vitamin A supplementation for mother and infant may be associated with increased risk of mortality.
We don't know whether micronutrients are effective in prevention of MTCT of HIV as we found no RCT evidence on this outcome.
Avoidance of breastfeeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education. The risk of breastfeeding-related HIV transmission needs to be balanced against the multiple benefits that breastfeeding offers. In resource-poor countries, breastfeeding is strongly associated with reduced infant morbidity and improved child survival. Exclusive breastfeeding during the first 6 months may reduce the risk of HIV transmission compared with mixed feeding, while retaining most of its associated benefits.In a population where prolonged breastfeeding is usual, early, abrupt weaning may not reduce MTCT or HIV-free survival at 2 years compared with prolonged breastfeeding, and may be associated with a higher rate of infant mortality for those infants diagnosed as HIV-infected at <4 months of age. Antiretrovirals given to the mother or the infant during breastfeeding can reduce the risk of HIV transmission in the postpartum period. World Health Organization guidelines recommend that HIV-positive mothers should exclusively breastfeed for the first 6 months, after which time appropriate complementary foods can be introduced. Breastfeeding should be continued for the first 12 months of the infant's life, and stopped only when an adequate diet without breast milk can be provided. Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
PMCID: PMC3217724  PMID: 21477392
17.  Human lipodystrophies: genetic and acquired diseases of adipose tissue 
Endocrine Development  2010;19:1-20.
Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2 (AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARγ. Importantly, lamin A/C mutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level.
Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their aetiology is generally unknown, they could be associated with signs of auto-immunity.
The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess.
Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardio-vascular and hepatic complications.
PMCID: PMC3892722  PMID: 20551664
1-Acylglycerol-3-Phosphate O-Acyltransferase; genetics; Adipose Tissue; pathology; physiopathology; Humans; Lamin Type A; genetics; Lipodystrophy; genetics; pathology; physiopathology; PPAR gamma; genetics
18.  HIV/AIDS and lipodystrophy: Implications for clinical management in resource-limited settings 
Lipodystrophy is a term used to describe a metabolic complication of fat loss, fat gain, or a combination of fat loss and gain, which is associated with some antiretroviral (ARV) therapies given to HIV-infected individuals. There is limited research on lipodystrophy in low- and middle-income countries, despite accounting for more than 95% of the burden of HIV/AIDS. The objective of this review was to evaluate the prevalence, pathogenesis and prognosis of HIV-related lipoatrophy, lipohypertrophy and mixed syndrome, to inform clinical management in resource-limited settings.
We conducted a structured literature search using MEDLINE electronic databases. Relevant MeSH terms were used to identify published human studies on HIV and lipoatrophy, lipohypertrophy, or mixed syndrome in low-, low-middle- and upper-middle-income countries through 31 March 2014. The search resulted in 5296 articles; after 1599 studies were excluded (958 reviews, 641 non-human), 3697 studies were extracted for further review. After excluding studies conducted in high-income settings (n=2808), and studies that did not meet inclusion criteria (n=799), 90 studies were included in this review.
Results and Discussion
Of the 90 studies included in this review, only six were from low-income countries and eight were from lower middle-income economies. These studies focused on lipodystrophy prevalence, risk factors and side effects of antiretroviral therapy (ART). In most studies, lipodystrophy developed after the first six months of therapy, particularly with the use of stavudine. Lipodystrophy is associated with increased risk of cardiometabolic complications. This is disconcerting and anticipated to increase, given the rapid scale-up of ART worldwide, the increasing number and lifespan of HIV-infected patients on long-term therapy, and the emergence of obesity and non-communicable diseases in settings with extensive HIV burden.
Lipodystrophy is common in resource-limited settings, and has considerable implications for risk of metabolic diseases, quality of life and adherence. Comprehensive evidence-based interventions are urgently needed to reduce the burden of HIV and lipodystrophy, and inform clinical management in resource-limited settings.
PMCID: PMC4297925  PMID: 25598476
HIV; AIDS; lipodystrophy; fat redistribution; antiretroviral therapy
19.  Prevalence of lipodystrophy and metabolic syndrome among HIV positive individuals on Highly Active Anti-Retroviral treatment in Jimma, South West Ethiopia 
Use of highly active antiretroviral therapy has led to significant reductions in morbidity and mortality rates. However, these agents had also given rise to the metabolic and morphologic abnormalities which are modifiable risk factors for cardiovascular diseases. Evidences elsewhere indicate growing in prevalence of these problems but studies are lacking in Ethiopia. This study was conducted to determine the prevalence of HIV-associated lipodystrophy and metabolic syndrome in patients taking highly active antiretroviral therapy.
A cross-sectional study was conducted in 2010 on a sample of 313 patients taking highly active antiretroviral therapy in Jimma University specialized hospital. Structured questionnaire was used to assess patients’ sociodemographic characteristics and clinical manifestations of metabolic abnormalities. Checklists were used for reviewing charts about clinical manifestations of metabolic abnormalities and immunologic profile of patients. Data was cleaned, entered in and analyzed using SPSS for windows version 16.0.
Metabolic syndrome was detected in 21.1% and HIV-lipodystrophy was detected 12.1% of patients. The factors found to be independently associated with metabolic syndrome were taking the antiretroviral therapy for more than 12 months (AOR=4.2; 95% CI=1.24–14.23) and female sex (AOR=2.30; 95% CI=1.0–5.27) and the factor found to be independently associated with HIV-lipodystrophy was taking the antiretroviral therapy (AOR=3.59; 95% CI=1.03–12.54) for more than 12 months.
Metabolic abnormalities were relatively common in the study population. The problems were higher among those who took anti-retroviral treatment for longer duration. Therefore, regular screening for and taking action against the metabolic abnormalities is mandatory.
PMCID: PMC3542806  PMID: 23330034
HIV-lipodystrophy; metabolic syndrome; anti-retroviral
20.  Efavirenz-induced gynecomastia in a prepubertal girl with human immunodeficiency virus infection: a case report 
BMC Pediatrics  2013;13:120.
Prepubertal gynecomastia is a rare condition and most frequently classified as idiopathic. In HIV-infected adults gynecomastia is a recognised but infrequent side-effect of antiretroviral treatment (ART) and mostly attributed to efavirenz use. Gynecomastia should be distinguished from pseudogynecomastia as part of the lipodystrophy syndrome caused by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to avoid incorrect substitution of drugs. In the medical literature only five cases of prepubertal gynecomastia in children taking ART are described and underlying pathogenesis was unknown. The occurrence of adverse effects of ART may interfere with therapy adherence and long-term prognosis and for that reason requires attention. We report the first case of prepubertal gynecomastia in a young girl attributed to efavirenz use.
Case presentation
A seven-year-old African girl presented with true gynecomastia four months after initiation on ART (abacavir, lamivudine, efavirenz). History, physical examination and laboratory tests excluded known causes of gynecomastia and efavirenz was considered as the most likely cause. Six weeks after withdrawal of efavirenz the breast enlargement had completely resolved.
Efavirenz-induced gynecomastia may occur in children as well as in adults. With the increasing access to ART, the possibility of efavirenz-exposure and the potential occurrence of its associated side-effects may be high. In resource-poor settings, empirical change from efavirenz to nevirapine may be considered, providing no other known or alarming cause is identified, as efavirenz-induced gynecomastia can resolve quickly after withdrawal of the drug. Timely recognition of gynecomastia as a side-effect of efavirenz is important in order to intervene while the condition may still be reversible, to sustain adherence to ART and to maintain the sociopsychological health of the child.
PMCID: PMC3751361  PMID: 23941256
Gynecomastia; HIV; Efavirenz; Child; Prepubertal
21.  Patient Retention in Antiretroviral Therapy Programs in Sub-Saharan Africa: A Systematic Review 
PLoS Medicine  2007;4(10):e298.
Long-term retention of patients in Africa's rapidly expanding antiretroviral therapy (ART) programs for HIV/AIDS is essential for these programs' success but has received relatively little attention. In this paper we present a systematic review of patient retention in ART programs in sub-Saharan Africa.
Methods and Findings
We searched Medline, other literature databases, conference abstracts, publications archives, and the “gray literature” (project reports available online) between 2000 and 2007 for reports on the proportion of adult patients retained (i.e., remaining in care and on ART) after 6 mo or longer in sub-Saharan African, non-research ART programs, with and without donor support. Estimated retention rates at 6, 12, and 24 mo were calculated and plotted for each program. Retention was also estimated using Kaplan-Meier curves. In sensitivity analyses we considered best-case, worst-case, and midpoint scenarios for retention at 2 y; the best-case scenario assumed no further attrition beyond that reported, while the worst-case scenario assumed that attrition would continue in a linear fashion. We reviewed 32 publications reporting on 33 patient cohorts (74,192 patients, 13 countries). For all studies, the weighted average follow-up period reported was 9.9 mo, after which 77.5% of patients were retained. Loss to follow-up and death accounted for 56% and 40% of attrition, respectively. Weighted mean retention rates as reported were 79.1%, 75.0% and 61.6 % at 6, 12, and 24 mo, respectively. Of those reporting 24 mo of follow-up, the best program retained 85% of patients and the worst retained 46%. Attrition was higher in studies with shorter reporting periods, leading to monthly weighted mean attrition rates of 3.3%/mo, 1.9%/mo, and 1.6%/month for studies reporting to 6, 12, and 24 months, respectively, and suggesting that overall patient retention may be overestimated in the published reports. In sensitivity analyses, estimated retention rates ranged from 24% in the worse case to 77% in the best case at the end of 2 y, with a plausible midpoint scenario of 50%.
Since the inception of large-scale ART access early in this decade, ART programs in Africa have retained about 60% of their patients at the end of 2 y. Loss to follow-up is the major cause of attrition, followed by death. Better patient tracing procedures, better understanding of loss to follow-up, and earlier initiation of ART to reduce mortality are needed if retention is to be improved. Retention varies widely across programs, and programs that have achieved higher retention rates can serve as models for future improvements.
Almost half of people entering African HIV treatment programs were lost to follow-up or died within two years, according to this systematic review by Sydney Rosen and colleagues.
Editors' Summary
About 25 million people in sub-Saharan Africa are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Every year, about three million more people become infected with HIV and 2 million die from AIDS in this region, where the pandemic has reduced life expectancy, orphaned many children, and reversed economic growth. Since 1996, HIV-positive people living in wealthier parts of the world have had access to cocktails of antiretroviral drugs that hold HIV in check and allow them to live relatively normal, healthy lives. But these drugs are expensive and it is only in the past five years that antiretroviral therapy (ART) programs have been initiated in sub-Saharan Africa, often with international support.
Why Was This Study Done?
For ART to work, HIV-infected individuals whose immune systems have been damaged by the virus have to take antiretroviral drugs regularly for the rest of their lives. If people take ART irregularly or stop taking their medications they may become sicker or die, or the viruses they carry may become resistant to antiretroviral drugs. Several studies have looked at how well patients on ART stick to their day-to-day medication schedules, but how long patients stay in treatment programs, which they must do to prevent illness and death from AIDS, has received little attention. In this study the researchers reviewed reports of whether patients stay in treatment in ART programs in sub-Saharan Africa, and also looked at the reasons why they drop out.
What Did the Researchers Do and Find?
The researchers identified 32 scientific reports published or presented at meetings between 2000 and 2007 that gave details of the proportion of adult patients retained (alive and receiving ART) in ART treatment programs (not including research studies) in 13 countries in sub-Saharan Africa. The average follow-up time of the programs (adjusted for number of patients in each) was 9.9 months. At this time, 77.5% of the patients were retained on average. Of the patients not retained, just under half had died and half had been lost to follow up. That is, they had missed clinic visits or had not picked up their medication. Estimated average retention rates at 6, 12, and 24 months were 79.08%, 75% and 61.6%, respectively; retention rates reported at 24 months ranged between 46% and 85% of patients. Finally, using sensitivity analysis (a technique that can estimate best- and worst-case possibilities), the researchers estimated that actual retention in ART programs after 2 years probably lies between one-quarter and three-quarters of patients.
What Do These Findings Mean?
These results show that roughly half of people starting HIV treatment programs in Africa are no longer receiving treatment after two years. The overall success rates of African treatment programs may actually be even lower, if one takes into account that programs with very low retention may be unlikely to publish their results. This study therefore indicates that a worrying number of patients in sub-Saharan Africa who need ART are lost from treatment programs. Because many of these patients are lost because they die from AIDS, one way to improve retention might be to start treating people with ART earlier, before they become seriously ill from HIV. Better efforts to find out exactly why patients drop out of programs (for example, the cost of drugs and/or of transport to clinics) might reduce the number of patients lost to follow up. The researchers also suggest that ART programs with very high retention rates might serve as models to improve retention rates in other programs.
Additional Information.
Please access these Web sites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite is a regional page on sub-Saharan Africa from the University of California, San Francisco
Information is provided by the US Centers for Disease Control and Prevention on the US President's Emergency Plan for AIDS Relief in various countries and regions
Avert is an international AIDS charity that provides information on HIV and AIDS in Africa
Aidsmap is an international AIDS organization that summarizes research about HIV/AIDS and reports news (in English, Spanish, Portuguese, French, and Russian)
PMCID: PMC2020494  PMID: 17941716
22.  Immune reconstitution inflammatory syndrome presenting as chylothorax in a patient with HIV and Mycobacterium tuberculosis coinfection: a case report 
BMC Infectious Diseases  2010;10:321.
Patients with human immunodeficiency virus (HIV) infection are at risk for Mycobacterium tuberculosis (TB) coinfection. The advent of antiretroviral therapy restores immunity in HIV-infected patients, but predisposes patients to immune reconstitution inflammatory syndrome (IRIS).
Case Presentation
A 25-year-old HIV-infected male presented with fever, productive cough, and body weight loss for 2 months. His CD4 cell count was 11 cells/μl and HIV-1 viral load was 315,939 copies/ml. Antituberculosis therapy was initiated after the diagnosis of pulmonary TB. One week after antituberculosis therapy, antiretroviral therapy was started. However, multiple mediastinal lymphadenopathies and chylothorax developed. Adequate drainage of the chylothorax, suspension of antiretroviral therapy, and continued antituberculosis therapy resulted in successful treatment and good outcome.
Chylothorax is a rare manifestation of TB-associated IRIS in HIV-infected patients. Careful monitoring for development of IRIS during treatment of HIV-TB coinfection is essential to minimize the associated morbidity and mortality.
PMCID: PMC2988055  PMID: 21059235
23.  Ethnic and Constitutional Differences and their Relation to Breast Diseases in Israel: Educational and Socio-Economic Status 
British Journal of Cancer  1971;25(3):428-440.
An Israeli Jewish population group consisting of 1298 cases of breast cancer and 1816 cases of benign mastopathy hospitalized in 1960-64 and 10,604 properly selected control women was studied with respect to the relationship of breast diseases to ethnic origin, educational background and socio-economic status. It was found that the percentage of Israeli-born and Orientals was higher in the benign mastopathy group than in the cancer group. For the Westerners the opposite was true. Educational level and socio-economic status were considerably higher in patients than in controls, regardless of ethnic origin. They were also higher in Westerners than in Orientals and among the Orientals higher in Iraqis than in Yemenites. The population groups with high breast cancer incidence rate appear to be on a higher educational and socio-economic level than those with a low incidence rate.
PMCID: PMC2008736  PMID: 5144517
24.  Brain localization of Kaposi’s sarcoma in a patient treated by combination antiretroviral therapy 
BMC Infectious Diseases  2013;13:600.
Central nervous system is a very rare site of Kaposi’s sarcoma in acquired immunodeficiency syndrome. Kaposi’s sarcoma, a neoplasm of endothelial origin, occurs mainly in the skin, but can involve many tissues, especially in patients with a poor immunity. Combination antiretroviral therapy, highly active against human immunodeficiency virus type-1, has caused a dramatic reduction of cutaneous and visceral involvements. No report of central nervous system localization of Kaposi’s sarcoma is described since the introduction of combination antiretroviral therapy in the late 90’s.
Case presentation
A 42 year-old Caucasian man affected by human immunodeficiency virus type-1 infection treated with combination antiretroviral therapy and showing relatively preserved immunity with low viral load presented gingival squamous cell carcinoma and visceral (lungs and lymph nodes) Kaposi’s sarcoma. Chemotherapy and radiotherapy were performed with improvement of both neoplasms. Afterwards, a magnetic resonance imaging showed focal lesions of the brain. Despite new chemotherapy and radiotherapy the patient died. Histology after autopsy revealed brain lesions due to Kaposi’s sarcoma with the detection of Human Herpesvirus 8 on tissue samples.
This is the first report in the combination antiretroviral therapy era of a very rare complication of Kaposi’s sarcoma, such as that of brain localization, in a patient with a relatively good control of human immunodeficiency virus infection. Therefore, Kaposi’s sarcoma should be considered in differential diagnosis with other intracranial mass lesions that can occur in human immunodeficiency virus infected-patients focusing the issue of appropriate treatment for central nervous system involvement.
PMCID: PMC3878088  PMID: 24359263
Kaposi’s sarcoma; HHV-8; HIV; Combination antiretroviral therapy; Central nervous system
25.  Evaluation and Management of Dyslipidemia in Patients with HIV Infection 
Persons with HIV infection develop metabolic abnormalities related to their antiretroviral therapy and HIV infection itself. The objective of this study was to summarize the emerging evidence for the incidence, etiology, health risks, and treatment of dyslipidemias in HIV disease.
Systematic review of original research with quantitative synthesis.
Dyslipidemia is common in persons with HIV infection on highly active antiretroviral therapy (HAART), but methodologic differences between studies preclude precise estimates of prevalence and incidence. The typical pattern includes elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides, which may be markedly elevated. The dyslipidemia may be associated with lipodystrophy, insulin resistance, and, rarely, frank diabetes mellitus. Exposure to protease inhibitors (PIs) is associated with this entire range of metabolic abnormalities. PI-naïve patients on nucleoside reverse transcriptase inhibitors (NRTIs) may develop lipodystrophy, insulin resistance, hypercholesterolemia, and possibly modest elevations in triglycerides but not severe hypertriglyceridemia, which appears to be linked to PIs alone. Most studies have not found an association between CD4 lymphocyte count or HIV viral load and lipid abnormalities. The pathogenesis is incompletely understood and appears to be multifactorial. There are insufficient data to definitively support an increased coronary heart disease risk in patients with HIV-related dyslipidemia. However, some of the same metabolic abnormalities remain firmly established risk factors in other populations. Patients on HAART with severe hypertriglyceridemia may develop pancreatitis or other manifestations of the chylomicronemia syndrome. Some of the metabolic derangements (particularly hypertriglyceridemia) may improve upon replacing a PI with a non-nucleoside reverse transcriptase inhibitor. The limited experience suggests that fibrates, pravastatin, and atorvastatin can safely treat lipid abnormalities in HIV-infected patients.
Patients with HIV infection on HAART should be screened for lipid disorders, given their incidence, potential for morbidity, and possible long-term cardiovascular risk. Treatment decisions are complex and must include assessments of cardiac risk, HIV infection status, reversibility of the dyslipidemia, and the effectiveness and toxicities of lipid-lowering medications. The multiple potential drug interactions with antiretroviral or other HIV-related medications should be considered in lipid-lowering drug selection and monitoring.
PMCID: PMC1495116  PMID: 12390557
hyperlipidemia; triglycerides; HIV; lipodystrophy; protease inhibitors; HAART

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