Higher-Than-Expected Rates of Lactic Acidosis Among Highly Active Antiretroviral Therapy-Treated Women in Botswana

Wester, Carolyn; Okezie, Okechukwu A; Thomas, Ann; Bussmann, Hermann; Moyo, Sikhulile; Muzenda, Tanaka; Makhema, Joseph; Widenfelt, Erik van; Musonda, Rosemary; Novitsky, Vladimir; Gaolathe, Tendani; Ndwapi, Ndwapi; Essex, Max; Kuritzkes, Daniel R.; DeGruttola, Victor; Marlink, Richard

doi:10.1097/qai.0b013e3181568e3f

Cited by 71 publications

(82 citation statements)

References 21 publications

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“…A 2007 study found a similar percentage of lipodystrophy (34.2z) among Rwandan population of 409 adults (25) while Botswana study reported only 16z (26). A study in India, Kumarasamy et al reported a 42z incidence of skin rashes, which was much higher than that in our study (18.8z).…”

Section: Discussioncontrasting

confidence: 55%

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

Khan

Sulaiman

et al. 2016

Jpn J Infect Dis

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SUMMARY: 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 (76.9z) were men, and 172 (23.1z) were women. Overall 314 (42.2z) patients experienced ADRs. A total of 425 ADRs were reported, with 311 (73.1z) occurring in men and 114 (26.8z) in women, with a significant statistical relationship (P value (P) ＝ 0.02, OR ＝ 1.21). Overall 239 (56.2z) ADRs were recorded among Chinese, 94 (22.1z) in Malay, and 71 (16.7z) 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 (35.5z) followed by skin rashes in 80 (18.8z), anemia in 74 (17.4z), and peripheral neuropathy in 27 (6.3z) patients. These findings suggest a need of intensive monitoring of ADRs in HIV treatment centres across Malaysia.

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Section: Discussioncontrasting

confidence: 55%

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

Khan

Sulaiman

et al. 2016

Jpn J Infect Dis

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“…Hence it is conceivable from this study that there is no association between CD4 count and SHL/ LA among the SA population, in good agreement with the reports of Osler and others. [11,27] However, our findings contradict the results obtained by some researchers, in which a strong association between patient age [25] and CD4 count [24,26] and SHL/LA was observed. Several POLG1 mutations have been studied, resulting in deletions or point mutations in mtDNA and decreased polymerase activity.…”

Section: Researchcontrasting

confidence: 57%

“…These risk factors are consistent with those reported by other studies in related settings, [10,12,14] as well as in other studies globally. [8,15,[24][25][26] In this study, the baseline age of the cases and controls was significantly different (p=0.015), with a median age of 38 (IQR 33 -45) and 33 (IQR 28 -40) years for cases and controls, respectively. This is in good agreement with studies that have shown associations between SHL/ LA and advanced age.…”

Section: Researchmentioning

confidence: 96%

“…This is in good agreement with studies that have shown associations between SHL/ LA and advanced age. [24,25] Other studies have reported low baseline CD4 count [12,24,26] as a factor associated with SHL/LA. In this study, the controls had a lower baseline CD4 count median, of 89 cells/µL (IQR 26 -170) compared with 121 cells/µL (IQR 56 -156) in cases, at the time of hyperlactataemia diagnosis.…”

Section: Researchmentioning

confidence: 99%

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Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa

et al. 2016

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Background. Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA. Objective. To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/ LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy. Methods. One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results. Results. Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p<0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 -114.25) compared with males. Conclusion. This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA.

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“…Lactic acidosis, a rare but life-threatening mitochondrial toxicity associated with long-term NRTI use, occurs approximately 20-fold more frequently in women (31,41), suggesting possible sex-based differences in NRTI cellular pharmacology. Current data regarding associations between the cellular pharmacology of these drugs and sex are variable and inconclusive.…”

mentioning

confidence: 99%

Effect of HIV-1 Infection and Sex on the Cellular Pharmacology of the Antiretroviral Drugs Zidovudine and Lamivudine

Rower

Meditz

Gardner

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTThe cellular pharmacology of zidovudine (ZDV) and lamivudine (3TC)in vivois not completely understood. This prospective longitudinal study investigated the relationship between HIV-1 serostatus, sex, race, and time on therapy with intracellular and plasma ZDV and 3TC concentrations. Of 20 HIV-seronegative and 23 HIV-seropositive volunteers enrolled, 16 (8 women) and 21 (5 women) completed all 12 study days, respectively. Volunteers began ZDV-3TC therapy (plus a third active drug in HIV-seropositive volunteers), and steady-state concentrations (Css) were determined after days 1, 3, 7, and 12. A repeated-measures mixed model was utilized. HIV-seronegative status was associated with 22% (95% confidence interval [CI], 0%, 50%) and 37% (15%, 67%) higherCssestimates compared to those of HIV-seropositive individuals for intracellular ZDV-TP and 3TC-TP levels, respectively. African-Americans had 36% (8%, 72%) higher ZDV-TP estimates than non-African-Americans. Sex was not associated with ZDV-TP or 3TC-TP (P> 0.19). Women had 36% (4%, 78%) higher plasma ZDV, but the effect was lessened when normalized by lean body weight (5% [−19%, 38%];P= 0.68). Plasma 3TC was 19% (0%, 41%) higher in HIV-seropositive volunteers and 22% (0%, 48%) higher in African American volunteers, but these effects were not significant when corrected for creatinine clearance (7% [−9%, 20%] and −5% [−26%, 12%] for HIV serostatus and race, respectively;P> 0.35). These results suggest that HIV-seropositive status decreases and African American race elevates the cellular triphosphates of ZDV and 3TC. This information extends knowledge of ZDV and 3TC cellular pharmacologyin vivoand provides new leads for future cellular pharmacology studies aimed at optimizing HIV prevention/treatment with these agents.

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Higher-Than-Expected Rates of Lactic Acidosis Among Highly Active Antiretroviral Therapy-Treated Women in Botswana

Cited by 71 publications

References 21 publications

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

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

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa

Effect of HIV-1 Infection and Sex on the Cellular Pharmacology of the Antiretroviral Drugs Zidovudine and Lamivudine

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