HIV and adipose tissue: A long history linked to therapeutic classes of antiretrovirals.

HIV infection has been controlled only since the introduction of triple therapy in 1996, combining, as antiretroviral agents, two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI). However, among the NRTIs, the thymidine analogues stavudine and zidovudine led to lipoatrophy, either generalized or associated with visceral fat hypertrophy and buffalo hump. These molecules also increased insulin resistance and the prevalence of diabetes. They were replaced by other NRTIs or non-NRTIs (NNRTIs) that were considered to be free of adipose tissue (AT) toxicity. More recently, the NRTI tenofovir disoproxyfumarate (TDF) and the NNRTI efavirenz have been associated with inhibition of fat gain but not with clear lipoatrophy. Otherwise, the use of PIs led to a phenotype of trunk fat hypertrophy associated with cardiometabolic complications. To avoid their adverse effects, PIs have recently been replaced by a new class of antiretrovirals, the integrase inhibitors (INSTIs), which are well tolerated and effective in controlling HIV. However, this class has been associated with global weight gain, which may be important and concerning for some people living with HIV (PWH). Also, in the NRTI class, TDF has often been replaced by tenofovir alafenamide (TAF) due to bone and renal toxicities, and TAF has been associated with global fat gain. The cardiometabolic consequences of INTIs and TAF are primarily related to the associated weight gain. In the global obesogenic worldwide context, PWH are gaining weight as well in relation to poor health life conditions. Taking in charge obesity uses the same strategies as those used in the general population.

REVERSIBILITY OF LIPOATROPHY IN HIV-INFECTED PATIENTS TAKING ANTIRETROVIRAL THERAPY: A COHORT STUDY WITH ULTRASOUND ASSESSMENT.

The aim of this study was to characterize and compare changes in subcutaneous fat in the malar, brachial and crural region in a cohort of HIV-infected patients taking antiretroviral therapy. This prospective longitudinal study included 77 patients who were selected from the initial cohort evaluated in 2007 and 2008. We examined reversibility of lipoatrophy measured by ultrasound over at least five-year period and factors related to its reversibility. All 46 patients who used stavudine switched from stavudine to another combination. Of 58 patients on zidovudine, 16 (28%) were on a zidovudine based regimen at the second follow up. There was evidence for subcutaneous fat increase in the malar area (p<0.001) and no increase in the brachial and crural areas. Patients who were smokers and had poor adherence to the Mediterranean diet had a thinner malar area at the follow up measurement (p=0.030) and smaller increase in subcutaneous malar fat compared to others (p=0.040). Our study suggested that modest increase of subcutaneous fat in malar area coincided with stopping stavudine and fewer usage of zidovudine. Lifestyle with non-adherence to the Mediterranean diet and smoking were associated with a smaller increase in subcutaneous malar fat.

Lipodystrophic syndrome of HIV and associated factors: a study in a university hospital. / Síndrome lipodistrófica do HIV e seus fatores associados: um estudo em um hospital universitário.

The use of antiretroviral drugs has increased the survival of HIV patients, but may have side effects, such as lipodystrophic syndrome. This article aims to identify the frequency of the lipodystrophic syndrome and its associated factors in patients with HIV using antiretroviral therapy. It involved a cross-sectional study with HIV patients, monitored on an outpatient basis. The syndrome was evaluated by the association of two parameters: peripheral weight loss through the lipodystrophy severity scale and central fat accumulation, measured by the hip waist ratio. Poisson regression analysis was performed to identify the associated variables. Of the 104 patients evaluated, 27.9% presented the syndrome. After adjustment, the female sex (PRadjusted = 2.16 CI95% 1.43-3.39), being overweight (PRadjusted = 2.23 CI95% 1.35-2.65) and a longer period of use of antiretrovirals (PRadjusted = 1.64 CI95% 1.16-2.78), remained positively associated with the syndrome. On the other hand, a negative association with CD4 count £ 350 (PRadjusted = 0.39 CI95% 0.10-0.97) was observed The high prevalence of the syndrome and its association with specific groups reinforce the need for adequate follow-up and early identification to intervene in modifiable factors.

O uso de antirretroviral aumentou a sobrevida dos portadores do HIV, porém pode acarretar efeitos colaterais, como a síndrome lipodistrófica. O objetivo deste artigo é identificar a frequência da síndrome lipodistrófica e seus fatores associados em pacientes portadores do HIV em uso de terapia antiretroviral. Estudo transversal com pacientes acompanhados ambulatorialmente. A síndrome foi avaliada pela associação de dois parâmetros: emagrecimento periférico através da escala de gravidade de lipodistrofia e acúmulo de gordura central, mensurado pela relação cintura quadril. Para identificar as variáveis associadas foi realizada a análise de Regressão de Poisson. Dos 104 pacientes avaliados, 27,9% apresentaram a síndrome. Após ajuste, ser do sexo feminino (RPajustada = 2,16 IC95%1,43-3,39), ter excesso de peso (RPajustada = 2,23 IC95%1,35-2,65) e um maior tempo de uso dos antirretrovirais (RPajustada = 1,64 IC95%1,16-2,78) permaneceram positivamente associados à síndrome. Por outro lado, foi observada uma associação negativa com a contagem de CD4 £ 350 (RPajustada = 0,39 IC95%0,10-0,97). A alta prevalência da síndrome e sua associação com grupos específicos reforçam a necessidade do adequado acompanhamento e identificação precoce como forma de intervir nos fatores modificáveis.

Síndrome lipodistrófica do HIV e seus fatores associados: um estudo em um hospital universitário / Lipodystrophic syndrome of HIV and associated factors: a study in a university hospital

Resumo O uso de antirretroviral aumentou a sobrevida dos portadores do HIV, porém pode acarretar efeitos colaterais, como a síndrome lipodistrófica. O objetivo deste artigo é identificar a frequência da síndrome lipodistrófica e seus fatores associados em pacientes portadores do HIV em uso de terapia antiretroviral. Estudo transversal com pacientes acompanhados ambulatorialmente. A síndrome foi avaliada pela associação de dois parâmetros: emagrecimento periférico através da escala de gravidade de lipodistrofia e acúmulo de gordura central, mensurado pela relação cintura quadril. Para identificar as variáveis associadas foi realizada a análise de Regressão de Poisson. Dos 104 pacientes avaliados, 27,9% apresentaram a síndrome. Após ajuste, ser do sexo feminino (RPajustada = 2,16 IC95%1,43-3,39), ter excesso de peso (RPajustada = 2,23 IC95%1,35-2,65) e um maior tempo de uso dos antirretrovirais (RPajustada = 1,64 IC95%1,16-2,78) permaneceram positivamente associados à síndrome. Por outro lado, foi observada uma associação negativa com a contagem de CD4 £ 350 (RPajustada = 0,39 IC95%0,10-0,97). A alta prevalência da síndrome e sua associação com grupos específicos reforçam a necessidade do adequado acompanhamento e identificação precoce como forma de intervir nos fatores modificáveis.

Abstract The use of antiretroviral drugs has increased the survival of HIV patients, but may have side effects, such as lipodystrophic syndrome. This article aims to identify the frequency of the lipodystrophic syndrome and its associated factors in patients with HIV using antiretroviral therapy. It involved a cross-sectional study with HIV patients, monitored on an outpatient basis. The syndrome was evaluated by the association of two parameters: peripheral weight loss through the lipodystrophy severity scale and central fat accumulation, measured by the hip waist ratio. Poisson regression analysis was performed to identify the associated variables. Of the 104 patients evaluated, 27.9% presented the syndrome. After adjustment, the female sex (PRadjusted = 2.16 CI95% 1.43-3.39), being overweight (PRadjusted = 2.23 CI95% 1.35-2.65) and a longer period of use of antiretrovirals (PRadjusted = 1.64 CI95% 1.16-2.78), remained positively associated with the syndrome. On the other hand, a negative association with CD4 count £ 350 (PRadjusted = 0.39 CI95% 0.10-0.97) was observed The high prevalence of the syndrome and its association with specific groups reinforce the need for adequate follow-up and early identification to intervene in modifiable factors.

Self-reported lipodystrophy, nutritional, lipemic profile and its impact on the body image of HIV-1-infected persons, with and without antiretroviral therapy.

A cross-sectional study was conducted with 227 adults, 162 using antiretroviral therapy (ART), both sexes, in Secondary Immunodeficiency Outpatient Clinic of the Department of Dermatology of the Hospital das Clínicas of the Faculty of Medicine of University of São Paulo. The patients were grouped into 92 under ART and self-reported lipodystrophy (G1); 70 under ART and without self-reported lipodystrophy (G2); 65 without ART (G3). We evaluated: (1) self-reported lipodystrophy, self-perception and feeling about body image; (2) Anthropometric and lipemic profile. We included 67% (n = 152) male; 33% (n = 77) female. There was a negative impact of self-reported lipodystrophy on body image, where female was more critical, although it was significant for male (p = 0.014). BMI revealed excess weight in female (p = 0.058). Hip waist ratio was shown to be a better parameter than abdominal perimeter when measuring fat in central region of male and lipohypertrophy was characterized in both sexes. There was lipoatrophy in upper and lower limbs for individuals of the (G1) and the male of this group presented hypertriglyceridemia, (p = 0.012). There was a difference in sex, pattern of self - perceived morphologic alterations and feeling in relation to body image when associated with self - reported lipodystrophy, ART use, anthropometric and lipemic profile.

Anthropometric definitions for antiretroviral-associated lipodystrophy derived from a longitudinal South African cohort with serial dual-energy X-ray absorptiometry measurements.

The development of lipodystrophy is associated with the long-term use of antiretroviral therapy (ART). We assessed agreement between patient-reported lipodystrophy and body composition measures using dual-energy X-ray absorptiometry (DXA) and developed objective measures to define lipoatrophy and lipohypertrophy in black South Africans. One hundred and eighty-seven ART-naïve HIV-infected adults were enrolled in a 24-month longitudinal study. Self-reported information on regional fat loss and fat gain, anthropometry, and DXA measures were collected at baseline, three, six, 12, 18, and 24 months after starting ART. Receiver operating characteristic curves were used to describe the performance of anthropometric variables using change in limb and trunk fat measured by DXA, as the reference standard. The proportion of men and women who developed lipoatrophy and lipohypertrophy increased over the 24-month period, with lipoatrophy occurring more frequently in men (21% versus 10%). In women, lipoatrophy was best determined by thigh skinfold thickness (80.3% correctly classified) and mid-arm circumference (77.6% correctly classified). None of the anthropometric measures performed well for defining lipoatrophy in men. Anthropometric measures performed well for defining lipoatrophy in women, but not lipohypertrophy.

"I don't want to look like an AIDS victim": A New Zealand case study of facial lipoatrophy.

The development of antiretroviral (ARV) drugs to treat HIV has turned what was once a death sentence into a chronic disorder. However, a focus on absence of disease in the form of an undetectable viral load and the dismissal of the so-called "cosmetic" complications of the disease ignores perceptions of health and well-being of those living with HIV. Facial lipoatrophy is a stigmatising side effect of treatment for HIV as it betrays the presence of the virus within the body. The study took a longitudinal qualitative approach, interviewing 11 people twice over a period of 1 year on their experience of living with HIV. Two participants were given cameras and asked to take photos which represented what it was like for them to live with this condition and were interviewed four times at four monthly intervals. This paper looks at one man's struggle to conceal or veil his facial lipoatrophy. His story is presented in the form of "selfies" and extracts from in-depth interviews. It tells of an emotional (ongoing) journey of frustration, anger, excitement, depression and resignation which had a profound effect on his sense of social and psychological well-being. This suggests a more holistic approach to treating people living with HIV is needed. While an undetectable viral load is indeed vital, it should not be seen as the only essential outcome of treatment.

Clinical and color Doppler ultrasound evaluation of polyacrylamide injection in HIV patients with severe facial lipoatrophy secondary to antiretroviral therapy.

BACKGROUND/PURPOSE: Facial lipoatrophy in HIV patients, secondary to antiretroviral therapy (ART) with thymidine analogs, has been related to important psychosocial alterations and poor adherence to treatment. Polyacrylamide gel (PAAG) is a filler that has been used for treating facial lipoatrophy in HIV patients. The aim was to assess the clinical and sonographic anatomical changes after injection of PAAG in HIV patients with facial lipoatrophy secondary to ART. METHODS: HIV patients receiving ART and suffering from severe facial lipoatrophy were recruited and underwent clinical and color Doppler ultrasound evaluation prior to PAAG application (AQUAMID® ) and sonographically monitored at 18 months and clinically followed up for 36 months after the procedure. Adverse effects were recorded based on occurrence and complexity. RESULTS: A total of 33 patients were evaluated, 30 men (91%) and 3 women (9%) with an average age of 49.6 years (±8.4). Clinical improvement assessed by a dermatologist had an average score of 5.9 (±0.7) on a scale of 1-7. On color Doppler ultrasound there was a significant increase of the thickness of the subcutaneous tissue (SCT) in both nasofold lines when comparing before and after PAAG injection (P < 0.01) and no signs of inflammation (hypervascularity). User satisfaction was qualified as excellent or good in all cases. Only two patients experienced adverse effects (hematoma and puncture site infection), which was successfully managed without consequences. CONCLUSION: Treatment of facial lipoatrophy with PAAG seems to be effective in HIV patients and no signs of complications were observed in the monitoring at 36 months after injection. Color Doppler ultrasound can identify the filler deposits and the anatomical changes of the SCT non-invasively.

Pioglitazone therapy for HIV/HAART-associated lipodystrophy syndrome could increase subcutaneous fat mass in non-lipoatrophic but not in lipoatrophic regions.

Highly active antiretroviral therapy (HAART) is associated with multiple metabolic disorders, including lipodystrophy, dyslipidaemia and insulin resistance. HIV/HAART-associated lipodystrophy syndrome (HALS) is characterised by subcutaneous fat wasting, central fat accumulation and increased risk of diabetes. Thiazolidinediones are considered a promising treatment for HALS, because they improve insulin sensitivity and increase subcutaneous fat mass. In previous studies, pioglitazone increased overall fat mass in patients with HALS but whether fat distribution changes remains unclear. We describe a HALS patient with diabetes treated with pioglitazone. Prior to pioglitazone therapy, he had hollowed cheeks, loss of fat in the extremities and abdominal obesity. 18 months after starting pioglitazone and switching his HAART regimens, T1-weighted MRI showed obvious increases in the subcutaneous fat mass of the neck and upper trunk, but no changes in the cheeks and extremities. Pioglitazone therapy for HALS could increase subcutaneous fat mass in non-lipoatrophic but not in lipoatrophic regions.

Adverse Drug Reactions in HIV/AIDS Patients at a Tertiary Care Hospital in Penang, Malaysia.

In the current study we explored the occurrence of adverse drug reactions (ADRs) to antiretroviral therapy among human immune-deficiency virus (HIV)/AIDS patients. We concluded an observational retrospective study in all patients who were diagnosed with HIV infection and were receiving highly active antiviral therapy from Jan. 2007 to Dec. 2012 at Hospital Pulau Pinang, Malaysia. Patient socio-demographic details along with clinical features and susceptible ADRs were observed during the study period. Out of 743 patients, 571 (76.9%) were men, and 172 (23.1%) were women. Overall 314 (42.2%) patients experienced ADRs. A total of 425 ADRs were reported, with 311 (73.1%) occurring in men and 114 (26.8%) in women, with a significant statistical relationship (P value (P) = 0.02, OR = 1.21). Overall 239 (56.2%) ADRs were recorded among Chinese, 94 (22.1%) in Malay, and 71 (16.7%) in Indian patients, which had a statistically significant association with ADRs (P = 0.05, OR = 1.50). Out of a total 425 among ADRs, lipodystrophy was recorded in 151 (35.5%) followed by skin rashes in 80 (18.8%), anemia in 74 (17.4%), and peripheral neuropathy in 27 (6.3%) patients. These findings suggest a need of intensive monitoring of ADRs in HIV treatment centres across Malaysia.

Effects of raltegravir combined with tenofovir/emtricitabine on body shape, bone density, and lipids in African-Americans initiating HIV therapy.

BACKGROUND: Raltegravir (RAL) plus tenofovir/emtricitabine (TDF/FTC) is a recommended initial antiretroviral regimen. A substantial proportion of persons diagnosed with HIV infection and starting antiretrovirals in the U.S. are African-American (AA); however, the effects of this regimen on metabolic parameters have largely been studied in white patients. METHODS: Single-arm, open-label study of untreated AA HIV-infected patients administered RAL with TDF/FTC for 104 weeks. Changes in fasting lipids, insulin resistance, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), limb and trunk fat, and bone mineral density (BMD) were assessed at weeks 56 and 104. RESULTS: Thirty (85% men) participants were included. Median entry characteristics included age of 38 years, CD4 323 cells/mm3, HIV RNA level 29,245 copies/ml, and body mass index 28.1 kg/m2. At 56 and 104 weeks, significant increases in VAT, trunk fat, limb fat, and overall fat were observed. Bone mineral density decreased by 1.5% by week 104.There were no significant changes in non-HDL-cholesterol, fasting triglycerides, or insulin resistance. A median CD4 cell count increase of 318 cells/mm3 (IQR 179, 403; full range 40, 749) (P<0.001) was observed. Assuming missing=failure, 78 and 70% had HIV RNA levels<40 copies/ml at weeks 56 and 104, respectively. There were no treatment-related discontinuations and no new antiretroviral resistance mutations were detected. CONCLUSIONS: In this cohort of AAs, initiation of RAL with TDF/FTC was associated with significant general increases in fat. Significant changes in lipids or insulin resistance were not observed and there was a small decline in BMD. Therapy was well tolerated and effective. These results are consistent with findings of studies of initial antiretroviral therapy in racially diverse cohorts and inform treatment selection for AA patients starting therapy for HIV infection.

Genome-Wide Association Study of HIV-Related Lipoatrophy in Thai Patients: Association of a DLGAP1 Polymorphism with Fat Loss.

HIV-related lipoatrophy (LA) is a major adverse drug effect among HIV patients receiving the antiretroviral drug stavudine (d4T) in Southeast Asia. Although the development of LA could be observed in almost all HIV patients administered d4T for extended periods, there is considerable variation in the duration required to develop LA within this patient population. This study aimed to identify host genetic polymorphisms affecting the rate of LA onset in Thai HIV patients. We performed a genome-wide association study of HIV-related LA among patients at the Bamrasnaradura Infectious Diseases Institute, Thailand. Genotypes of HIV patients who developed LA within 2 years of treatment were compared with those of patients who did not develop LA after at least 4 years of treatment (non-LA patients). Genotypes of 49 LA and 92 non-LA patients at 578,525 single nucleotide polymorphisms (SNPs) were determined by Illumina bead arrays. The TaqMan real-time PCR method was used in a replication study. Five SNPs in the bead arrays, which showed the lowest p values in a comparison of LA with non-LA patients, were further tested in independent and sex-matched subpopulations consisting of 95 LA and 95 non-LA patients. This replication study revealed a significant association of LA with an SNP (rs12964965) in the gene encoding the Disks Large Homolog-Associated Protein 1 (DLGAP1), even after the correction for five multiple comparisons. These results strongly suggested involvement of the DLGAP1 gene product in the development of LA in Thai HIV patients.

Magnetic resonance imaging evaluation of lipodystrophy in HIV-positive patients receiving highly active antiretroviral therapy.

We evaluated retrospectively an automated method for the separate detection of subcutaneous and visceral fat in the abdominal region by magnetic resonance studies in HIV-positive patients on highly active antiretroviral therapy. The patients were divided into four different groups: lipoatrophy, lipohypertrophy, mixed and the control group. The use of software for the automated detection of abdominal compartment visceral adipose tissue (VAT), total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) was compared to manual evaluation methods (fuzzy C-mean). The results of ROC analysis showed that the parameters, particularly the VAT, are better than the VAT/TAT and at identifying patients with the symptoms of abdominal fat accumulation. A sensitivity of 80.3% and a specificity of 79.5% resulted from a threshold VAT value of >87 cm(2). Moreover, the manual evaluation method was shown to provide greater values for VAT and the VAT/TAT ratio than those given by the automated method. In the present study, a rapid MRI protocol for the detection and assessment of the course of lipodystrophy was presented and tested on a group of patients with signs of HALS, as well as on an antiretroviral naïve control group.

Cardiac morbidity in an HIV-1 lipodystrophy patient cohort expressing the TNF-α-238 G/A single nucleotide gene polymorphism.

In the current study we investigated the prevalence of the TNF-α 238G/A single nucleotide polymorphism (SNP) of the TNF-α gene in the development of lipodystrophy among HIV-1 infected individuals who had been receiving antiretroviral therapy (ART) in the immunodeficiency clinics of the National AIDS Research Institute (NARI) at Pune, India. We assessed the association of this SNP with the development of lipoatrophy/dyslipidemia and insulin resistance in these patients and measured carotid intima thickening which is a surrogate marker for chronic cardiac morbidity. Our results show that the incidence of the TNF-α 238G/A SNP is ~ two fold higher in patients with lipodystrophy as compared to those without lipodystrophy. Patients with lipodystrophy demonstrated a higher likelihood of the development of metabolic syndrome as evident by increased insulin sensitivity and increased percentage (%) ß cell function. Further, a significant increase in left carotid intima thickness was observed in patients with lipodystrophy. Our study validates the association of the TNF-α 238G/A SNP allelic variant with the development of HIV- lipodystrophy via the modulation of TNF-α production, which contributes to dyslipidemia, increased lipolysis, increased insulin resistance, altered differentiation of adipocytes and increased carotid intima thickness. The contribution of genetic determinants such as the TNF-α 238G/A SNP to lipodystrophy, may provide insight into the mechanisms that underlie this disease condition and may be useful in the future for personalized therapy. Additionally, these findings will be useful in monitoring chronic cardiac morbidities among HIV infected individuals who express this SNP.

[Lopinavir/ritonavir in human immunodeficiency virus-infected women]. / Lopinavir/ritonavir en mujeres infectadas por el virus de la inmunodeficiencia humana.

There are clear sex-related biological differences between men and women. Diseases that affect the two sexes differently are studied separately. However, some diseases affect both men and women, but their incidence or outcome are clearly different. In human immunodeficiency virus infection, the potential differences in the effects of antiretroviral therapy are poorly characterized and few studies have been designed to elucidate these differences. Moreover, women are usually poorly represented in clinical trials of antiretroviral drugs.

Lopinavir/ritonavir en mujeres infectadas por el virus de la inmunodeficiencia humana / Lopinavir/ritonavir in human immunodeficiency virus-infected women

Existen claras diferencias biológicas entre varones y mujeres determinadas por razón de sexo; las enfermedades que inciden de manera diferenciada en varones y mujeres se estudian por separado. Sin embargo hay enfermedades que afectan a ambos sexos, pero cuya incidencia o evolución es marcadamente diferente. En la infección por el virus de la inmunodeficiencia humana, las potenciales diferencias en cuanto a los efectos del tratamiento antirretroviral no están bien estudiadas y hay pocos estudios diseñados con este fin; además, las mujeres, en general, están poco representadas en los ensayos clínicos de fármacos antirretrovirales (AU)

There are clear sex-related biological differences between men and women. Diseases that affect the two sexes differently are studied separately. However, some diseases affect both men and women, but their incidence or outcome are clearly different. In human immunodeficiency virus infection, the potential differences in the effects of antiretroviral therapy are poorly characterized and few studies have been designed to elucidate these differences. Moreover, women are usually poorly represented in clinical trials of antiretroviral drugs (AU)