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Brief Report: Vaginal Viral Shedding With Undetectable Plasma HIV Viral Load in Pregnant Women Receiving 2 Different Antiretroviral Regimens: A Randomized Clinical Trial.
Frenkel, LM, Morrison, RL, Fuller, TL, Gouvêa, MI, Benamor Teixeira, ML, Coombs, RW, Shapiro, DE, Mirochnick, M, Hennessey, R, Whitson, K, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(4):361-365
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Abstract
BACKGROUND Pregnant women using antiretrovirals (ARVs) may have persistent vaginal viral shedding, which could be associated with sexual and perinatal HIV transmission. However, there are scant data on vaginal viral load (VVL) in pregnant women with undetectable plasma viral load (PVL). METHODS This study was a post hoc analysis of an open-label randomized trial to evaluate the virologic response of 2 ART regimens. The participants were ART-naive women living with HIV initiating ART regimens between 20 and 36 weeks of pregnancy recruited at 19 clinical sites in 6 countries. Participants were randomized to receive 400 mg of raltegravir 2 times a day or 600 mg of efavirenz 4 times a day in addition to 150 mg of lamivudine and 300 mg of zidovudine 2 times a day. VVL and PVL tests were performed at every study visit. The primary outcome measures were HIV-1 PVL and VVL at maternal study week 4 and rates of perinatal HIV transmission. RESULTS A total of 408 were enrolled, of whom 323 had VVL samples 4 weeks after enrollment and were included in this analysis. Among women with undetectable/nonquantifiable PVL during ART, the overall rate of quantifiable VVL at week 4 was 2.54% (7/275). Of the 275 with nonquantifiable PVL, 99.1% (115/116) and 96.2% (153/159) had nonquantifiable VVL in the efavirenz and raltegravir arms, respectively. None of the 7 women with quantifiable VVL at the week 4 study visit transmitted HIV to their infants. CONCLUSIONS Detectable VVL in pregnant women with undetectable/nonquantifiable PVL while receiving ART was rare and not associated with perinatal HIV transmission.
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Inflammatory Myositis Secondary to Anti-Retroviral Therapy in a Child; Case Report and Review of the Literature.
Monaghan, M, Loh, C, Jones, S, Oware, A, Urankar, K, Roderick, M, Majumdar, A
Journal of neuromuscular diseases. 2021;(6):1089-1095
Abstract
Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25-200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis.Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25-200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.
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Vitamin D and Calcium Supplement Attenuate Bone Loss among HIVInfected Patients Receiving Tenofovir Disoproxil Fumarate/Emtricitabine/ Efavirenz: An Open-Label, Randomized Controlled Trial.
Boontanondha, P, Nimitphong, H, Musikarat, S, Ragkho, A, Kiertiburanakul, S
Current HIV research. 2020;(1):52-62
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Abstract
BACKGROUND Antiretroviral therapy (ART), especially with tenofovir disoproxil fumarate (TDF), has been associated with accelerated bone turnover and leads to significant bone loss. OBJECTIVE We aimed to determine the effect of vitamin D2 and calcium on bone mineral density (BMD) in HIV-infected patients receiving TDF/emtricitabine (FTC)/efavirenz (EFV). METHODS A prospective, open-label, randomized controlled study was conducted. Eligible patients were ART naïve HIV individuals who initiated TDF/FTC/EFV. The study group received supplementation with vitamin D2 and calcium carbonate, whereas the control group was administered only ART. The primary outcome was the percentage change in total hip BMD at week 24 compared with baseline. RESULTS A total of 18 patients were randomized (9 in each group). The mean (standard deviation; SD) total hip BMD significantly decreased from baseline in both groups, from 0.96 (0.14) g/cm2 to 0.93 (0.13) g/cm2 in the study group (p = 0.006) and from 0.87 (0.11) g/cm2 to 0.84 (0.11) g/cm2 in the control group (p = 0.004). The mean (SD) lumbar spine BMD significantly decreased from baseline in both groups, from 1.00 (0.13) g/cm2 to 0.97 (0.13) g/cm2 (p = 0.004) in the study group and from 0.90 (0.09) g/cm3 to 0.86 (0.08) g/cm2 in the control group (p = 0.006). At week 24, the mean (SD) lumbar spine BMD was significantly greater in the study group than in the control group (p = 0.042). However, there were no significant differences in the percentage change of total hip, lumbar spine, and femoral neck BMD between both groups. No adverse events were reported. In conclusion, as early as 24 weeks after TDF initiation, a significant decline in BMD was detected. CONCLUSION Vitamin D2 and calcium supplements should be considered for HIV-infected patients receiving TDF/FTC/EFV in a resource-limited setting where there are limited ART options (Clinicaltrials. gov NCT0287643).
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Therapeutic Drug Monitoring of HIV Antiretroviral Drugs in Pregnancy: A Narrative Review.
O'Kelly, B, Murtagh, R, Lambert, JS
Therapeutic drug monitoring. 2020;(2):229-244
Abstract
To date, therapeutic drug monitoring (TDM) has played an important role in the management of pregnant HIV patients on highly active antiretroviral therapy. Historically, in pregnant women living with HIV, the third agent in triple therapy has been either non-nucleoside reverse transcriptase inhibitors or protease inhibitors (PIs). PIs have been the preferred agents because of their robustness from the perspective of viral resistance and the dominant drug class for the management of HIV during pregnancy for the previous decade. As with many drugs used during pregnancy, pharmacokinetic changes decrease exposure to these agents as the pregnancy progresses. This can lead to viral escape at the time of pregnancy and ultimately increase the risk of mother-to-child transmission (MTCT) of HIV. TDM has been well-established for this class of highly active antiretroviral therapy, and appropriate dose adjustment studies have been performed. At present, there is a shift from the traditional treatment paradigm in pregnancy to a new drug class, integrase strand transfer inhibitors (INSTIs). Although INSTIs are affected by pharmacokinetic changes during pregnancy, they do not harbor the same issues with viral escape as seen with PIs at birth and in general eliminate the need for boosting with additional agents like ritonavir (r) and cobicistat (c) [bar elvitegravir (EVG)] that can lead to interactions with treatment of other common infections in HIV, including tuberculosis. Furthermore, INSTIs are the most successful medication for rapidly reducing the viral load (VL) in HIV patients, a useful factor where VL may be unknown, or in late presenters. These merits make INSTIs the best choice in pregnancy, although their use has been hindered in recent years by a report of neural tube defects from a large African study with dolutegravir (DTG). New data from Botswana and Brazil indicate that this risk is less significant than previously reported, necessitating further data to shed light on this critical issue. Current international guidelines including DHHS, EACS, WHO, and BHIVA (for patients with VLs >100,000 copies/mL or late presenters) now recommend INSTIs as first-line agents. The role of TDM in INSTIs shifts to cases of insufficient viral suppression with standard adherence measures, cases of drug-drug interactions, or cases where EVG/c is continued throughout pregnancy, and thus remains an important aspect of HIV care in pregnancy.
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Early Progression and Immune Reconstitution Inflammatory Syndrome During Treatment of Mild-To-Moderate Kaposi Sarcoma in Sub-Saharan Africa and South America: Incidence, Long-Term Outcomes, and Effects of Early Chemotherapy.
Nyirenda, M, Ngongondo, M, Kang, M, Umbleja, T, Krown, SE, Godfrey, C, Samaneka, W, Mngqibisa, R, Hoagland, B, Mwelase, N, et al
Journal of acquired immune deficiency syndromes (1999). 2020;(4):422-429
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Abstract
BACKGROUND Early progression of AIDS-associated Kaposi sarcoma (KS-PD) and immune reconstitution inflammatory syndrome (KS-IRIS) sometimes occur after the initiation of antiretroviral therapy (ART). METHODS Early KS-PD and KS-IRIS were assessed in the A5264/AMC-067 trial in which participants with mild-to-moderate AIDS-KS were randomized to initiate ART with either immediate or as-needed oral etoposide. Early KS-PD was defined as tumor progression within 12 weeks of ART initiation. When investigators had concern that early KS-PD was KS-IRIS, additional evaluations were performed. Suspected KS-IRIS was defined as early KS-PD accompanied by a CD4 count increase of ≥50 cells per cubic millimeter or plasma HIV-1 RNA decrease of ≥0.5 log10 copies/mL. Clinical outcome was a composite end point categorized as failure, stable, and response at 48 and 96 weeks compared with baseline. RESULTS Fifty of 190 participants had early KS-PD (27%): 28 had KS-IRIS and 22 were not evaluated for KS-IRIS. Early KS-PD and KS-IRIS incidences with immediate etoposide versus ART alone were 16% versus 39%, and 7% versus 21%, respectively. Week 48 clinical outcome was 45% failure, 18% stable, and 37% response for no early KS-PD; 82% failure, 2% stable, and 16% response for early KS-PD; and 88% failure, 0% stable, and 12% response for KS-IRIS. Cumulative incidence of KS tumor response by week 96 was 64% for no early KS-PD, 22% with early KS-PD, and 18% with KS-IRIS. CONCLUSIONS Early KS-PD, including suspected KS-IRIS, was common after starting ART for AIDS-KS and was associated with worse long-term clinical outcomes. Starting ART concurrently with etoposide reduced the incidence of both early KS-PD and KS-IRIS compared with ART alone.
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Causes of hypercalcemia in people living with HIV in the HAART era.
Nongnuch, A, Petcharut, J, Suksuwan, W, Davenport, A, Phuphuakrat, A
HIV research & clinical practice. 2020;(5):115-120
Abstract
BACKGROUND Hypercalcemia is an uncommon finding in people living with HIV (PLHIV). Causes of hypercalcemia in PLHIV have not been well documented. As such, we studied the causes of hypercalcemia in PLHIV. METHODS We conducted a retrospective review of PLHIV who had corrected serum calcium of ≥10.5 mg/dL between 2010 and 2019. Demographic data, associated diseases, and treatment details were collected. Corrected serum calcium levels were compared among the causes of hypercalcemia. RESULTS A total of 70 of 2168 (3.2%) PLHIV had hypercalcemia. Forty-nine (70.0%) were male with a mean age of 47.7 ± 4.7 years. Only two (2.9%) had symptoms of hypercalcemia. Fifty-four patients had identifiable causes of hypercalcemia; 21 infections (30.0%), 17 solid organ malignancies (24.3%), 14 hematologic malignancies (20.0%), and two other specific causes (2.9%). Mean corrected serum calcium concentrations of PLHIV who had solid organ malignancy, hematologic malignancy, infection, and unknown causes were 12.8 ± 2.1, 11.4 ± 1.0, 11.2 ± 0.6, and 10.8 ± 0.2 mg/dL, respectively. Corrected serum calcium levels were significantly greater in patients who had solid organ malignancy comparing to those with other causes of hypercalcemia (p < 0.05, all). Logistic regression identified solid organ malignancy as the only factor associated with moderate to severe hypercalcemia (odds ratio 12.72, 95% confidence interval 3.11-52.08; p < 0.001). CONCLUSIONS Hypercalcemia in PLHIV is associated with solid organ malignancy, hematologic malignancy, and infection. Most PLHIV with hypercalcemia are asymptomatic. Solid organ malignancy is associated with moderate to severe hypercalcemia, and as such PLHIV presenting with moderate to severe hypercalcemia should be investigated for solid organ malignancy.
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Anti-retroviral therapy failure in HIV-1 infected pregnant women and its associated risk of HIV transmission.
Bardeskar, NS, Ahir-Bist, SP, Mehta, PR, Samant-Mavani, P, Nanavati, R, Mania-Pramanik, J
Archives of gynecology and obstetrics. 2020;(5):1229-1235
Abstract
BACKGROUND The HIV perinatal transmission in India even after interventions is still high. The anti-retroviral therapy failure rate and the risk of HIV vertical transmission to infants from women with failed treatment during pregnancy also largely remains unevaluated. METHODS This is a prospective, observational and follow-up study of 18 months to determine the association of ART failure in pregnant women and the subsequent risk of HIV transmission to their infants. A total of 81 mothers were evaluated for ART success/failure by analysing their viral loads. RESULTS Analyses revealed that a high percentage (19.75%) of women on ART had high viral loads, while the overall HIV transmission rate to the infants was 8.64%. The rate of transmission from women with high viral load was significantly high compared to women with low viral load (37.5% vs. 1.54%; p = 0.0015). CD4 level was not associated with HIV transmission. However, CD4 levels in women, who had successful or failed ART, were significantly different (p = 0.0031). Factors such as mother's age, baby's sex and weight as well as delivery mode were not associated with HIV transmission, however, breastfeeding and viral loads were found to be independently associated with HIV transmission to the neonates. CONCLUSIONS This study highlights that a significant proportion of women on ART had impaired viral load control. The rate of HIV transmission to infants was also significantly high among these women. This warrants viral load monitoring of HIV infected women to reduce the overall transmission to the infants.
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Higher iron stores and the HFE 187C>G variant delay onset of peripheral neuropathy during combination antiretroviral therapy.
Kallianpur, AR, Wen, W, Erwin, AL, Clifford, DB, Hulgan, T, Robbins, GK
PloS one. 2020;(10):e0239758
Abstract
OBJECTIVE People with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today. DESIGN This time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART. METHODS Soluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders. RESULTS Of 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all p<0.05). Higher sTFR or iron stores, the HFE 187C>G variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-values<0.05), independent of age, CD4+ T-cell count, plasma HIV RNA, and cART regimen. CONCLUSIONS Higher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.
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Dietary nitrate improves skeletal muscle microvascular oxygenation in HIV-infected patients receiving highly active antiretroviral therapy: a randomised, double-blind, cross-over, placebo-controlled study.
Barros-Santos, E, de Oliveira, GV, Volino-Souza, M, Alvares, TS
The British journal of nutrition. 2020;(12):1277-1284
Abstract
HIV-1 proteins and highly active antiretroviral therapy (HAART) have been associated with microvascular endothelial dysfunction. Although nitrate-rich beetroot juice (NR-BJ) consumption has been shown to improve endothelial function in clinical population, its effects in HIV-infected patients has not been addressed. We investigated the effect of a single dose of NR-BJ on muscle oxygen saturation parameters in response to a handgrip exercise in HIV-infected patients. Fifteen HIV-infected patients received NR-BJ or nitrate-depleted beetroot juice (ND-BJ) in a double-blind cross-over design. Near-IR spectroscopy was utilised to assess muscle oxygen saturation parameters during rhythmic handgrip exercise after NR-BJ or ND-BJ supplementation. A significant faster muscle oxygen desaturation rate during exercise (-7·97 (sd 5·00) v. -5·45 (3·94) %/s, P = 0·005) and muscle oxygen resaturation rate during exercise recovery (0·43 (0·24) v. 0·28 (0·24) %/s, P = 0·030) after NR-BJ ingestion was found. However, no significant difference in exercise time until fatigue was observed. Salivary nitrite and urinary nitrate concentration were analysed after NR-BJ or ND-BJ. A significant increase in salivary nitrite and urinary nitrate in NR-BJ was observed compared with ND-BJ (P < 0·05). Our findings suggest that NR-BJ consumption may acutely improve muscle oxygen saturation during exercise and exercise recovery in HIV-infected patients undergoing HAART and who are expected to present microvascular damage. Thus, future studies investigating the chronic effects of NR-BJ are warranted to delineate a better nutritional strategy based on nitrate-rich foods.
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Hepatitis B virus coinfection is associated with high early mortality in HIV-infected Tanzanians on antiretroviral therapy.
Christian, B, Fabian, E, Macha, I, Mpangala, S, Thio, CL, Ulenga, N, Mugusi, F, Ammerman, LR, Fawzi, W, Green, R, et al
AIDS (London, England). 2019;(3):465-473
Abstract
OBJECTIVES There is limited data on the effect of antiviral therapies on clinical outcomes in HIV and hepatitis B virus (HBV)-infected individuals in sub-Saharan Africa. DESIGN Single center, prospective longitudinal cohort study at Management and Development for Health supported HIV Care and Treatment clinics in Dar es Salaam, Tanzania. METHODS Between April 2014 and December 2015, HIV-infected, HBV-infected and HIV/HBV-coinfected, treatment naïve, Tanzanian adults more than 18 years of age were eligible for enrollment and followed for 10-18 months after initiating antivirals. All HIV-infected and HIV/HBV-coinfected participants received tenofovir, lamivudine and efavirenz; HBV-infected participants received lamivudine. Multivariate regression models were constructed to identify factors associated with mortality in HIV-infected and HIV/HBV-coinfected participants. RESULTS A total of 265 HIV-infected, 165 HBV-infected and 64 HIV/HBV-coinfected participants were analyzed. At baseline, HBV-infected participants were younger and had a higher BMI than HIV-infected and HIV/HBV-coinfected participants. After a median of 371 (interquartile range 50) days on treatment, there were 40 deaths. Mortality was significantly higher among HIV/HBV-coinfected participants compared with HIV and HBV-infected participants [HIV/HBV-coinfected 12 of 64 (19%) vs. HIV-infected 26 of 265 (10%) and HBV-infected two of 265 (1%), P < 0.01]. High baseline HIV RNA and low hemoglobin levels, but not HBV coinfection were independently associated with early mortality in multivariate analyses of HIV-infected participants. CONCLUSION High rates of early mortality were observed after treatment initiation in HIV/HBV-coinfected individuals compared with participants with HIV or HBV alone, despite robust aspartate aminotransferase to platelet ratio index declines and high rates of virologic suppression. HIV rather than HBV-related factors are more important contributors to mortality in these individuals.