Articles tagged as "Zimbabwe"

Almost a quarter of deaths in pregnant and post-partum women may be attributable to HIV

Effect of HIV infection on pregnancy-related mortality in sub-Saharan Africa: secondary analyses of pooled community-based data from the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA).

Zaba B, Calvert C, Marston M, Isingo R, Nakiyingi-Miiro J, Lutalo T, Crampin A, Robertson L, Herbst K, Newell ML, Todd J, Byass P, Boerma T, Ronsmans C. Lancet. 2013 May 18;381(9879):1763-71.

Background: Model-based estimates of the global proportions of maternal deaths that are in HIV-infected women range from 7% to 21%, and the effects of HIV on the risk of maternal death is highly uncertain. We used longitudinal data from the Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA) network to estimate the excess mortality associated with HIV during pregnancy and the post-partum period in sub-Saharan Africa.

Methods: The ALPHA network pooled data gathered between June, 1989 and April, 2012 in six community-based studies in eastern and southern Africa with HIV serological surveillance and verbal-autopsy reporting. Deaths occurring during pregnancy and up to 42 days post partum were defined as pregnancy related. Pregnant or post-partum person-years were calculated for HIV-infected and HIV-uninfected women, and HIV-infected to HIV-uninfected mortality rate ratios and HIV-attributable rates were compared between pregnant or post-partum women and women who were not pregnant or post partum.

FINDINGS: 138,074 women aged 15-49 years contributed 636,213 person-years of observation. 49,568 women had 86,963 pregnancies. 6760 of these women died, 235 of them during pregnancy or the post-partum period. Mean prevalence of HIV infection across all person-years in the pooled data was 17.2% (95% CI 17.0-17.3), but 60 of 118 (50.8%) of the women of known HIV status who died during pregnancy or post partum were HIV infected. The mortality rate ratio of HIV-infected to HIV-uninfected women was 20.5 (18.9-22.4) in women who were not pregnant or post partum and 8.2 (5.7-11.8) in pregnant or post-partum women. Excess mortality attributable to HIV was 51.8 (47.8-53.8) per 1000 person-years in women who were not pregnant or post partum and 11.8 (8.4-15.3) per 1000 person-years in pregnant or post-partum women.

Interpretation: HIV-infected pregnant or post-partum women had around eight times higher mortality than did their HIV-uninfected counterparts. On the basis of this estimate, we predict that roughly 24% of deaths in pregnant or post-partum women are attributable to HIV in sub-Saharan Africa, suggesting that safe motherhood programmes should pay special attention to the needs of HIV-infected pregnant or post-partum women.

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Editor’s notes: This study is the first to estimate the contribution of HIV to mortality in pregnant and post-partum women using HIV sero-surveillance and verbal autopsy data from a network of studies in eastern and southern Africa. While there is variation by country, excess mortality due to HIV was considerably higher in non-pregnant women compared with pregnant/post-partum women. This is not entirely surprising as fertility falls with advancing HIV, so only healthier women with HIV conceive – the so-called ‘healthy pregnant woman effect’. They are therefore less likely to die while pregnant/post-partum. However, the study estimates that almost a quarter of deaths in pregnant/post-partum women are attributable to HIV. This highlights the importance of integrating HIV into safe motherhood programmes. It is noteworthy that the majority of women at the time of this study would not have had access to antiretroviral treatment to benefit their own health (as opposed to single dose treatment to reduce mother-to-child transmission alone). While pointing to the potential benefits of the WHO PMTCT B option, the study emphasizes the potential further advantage of PMTCT B+ to reduce HIV related morbidity and mortality, both for women’s own health and their unborn infants, with implications for current and future pregnancies.

Africa
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ARROW: monitoring strategies for management of ART in children

Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial

ARROW Trial team, Kekitiinwa A, Cook A, Nathoo K, Mugyenyi P et al. Lancet. 2013 Apr 20;381(9875):1391-403. doi: 10.1016/S0140-6736(12)62198-9. Epub 2013 Mar 7.

No trials have investigated routine laboratory monitoring for children with HIV, nor four-drug induction strategies to increase durability of first-line antiretroviral therapy (ART). In this open-label parallel-group trial, Ugandan and Zimbabwean children or adolescents with HIV, aged 3 months to 17 years and eligible for ART, were randomly assigned in a factorial design. Randomisation was to either clinically driven monitoring or routine laboratory and clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 cell counts; non-inferiority monitoring randomisation); and simultaneously to standard three-drug or to four-drug induction first-line ART, in three groups: three-drug treatment (non-nucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C; superiority ART-strategy randomisation). For patients assigned to routine laboratory monitoring, results were returned every 12 weeks to clinicians; for clinically driven monitoring, toxicity results were only returned for requested clinical reasons or if grade 4. Children switched to second-line ART for WHO stage 3 or 4 events or (routine laboratory monitoring only) age-dependent WHO CD4 criteria. Randomisation used computer-generated sequentially numbered tables incorporated securely within the database. Primary efficacy endpoints were new WHO stage 4 events or death for monitoring and change in CD4 percentage at 72 and 144 weeks for ART-strategy randomisations; the co-primary toxicity endpoint was grade 3 or 4 adverse events. Analysis was by intention to treat. 1 206 children were randomly assigned to clinically driven (n=606) versus routine laboratory monitoring (n=600), and groups A (n=397), B (n=404), and C (n=405). 47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (hazard ratio [HR] 1·13, 95% CI 0·73-1·73, p=0·59; non-inferiority criterion met). However, in years 2-5, rates were higher in children on clinically driven monitoring (1·3 vs 0·4 per 100 child-years, difference 0·99, 0·37-1·60, p=0·002). One or more grade 3 or 4 adverse events occurred in 283 (47%) children on clinically driven versus 282 (47%) on routine laboratory monitoring (HR 0·98, 0·83-1·16, p=0·83). Mean CD4 percentage change did not differ between ART groups at week 72 (16·5% [SD 8·6] vs 17·1% [8·5] vs 17·3% [8·0], p=0·33) or week 144 (p=0·69), but four-drug groups (B, C) were superior to three-drug group A at week 36 (12·4% [7·2] vs 14·1% [7·1] vs 14·6% [7·3], p<0·0001). Excess grade 3 or 4 events in groups B (one or more events reported by 157 [40%] children in A, 190 [47%] in B; HR [B:A] 1·32, 1·07-1·63) and C (218 [54%] children in C; HR [C:A] 1·58, 1·29-1·94; global p=0·0001) were driven by asymptomatic neutropenia in zidovudine-containing groups (B, C; 86 group A, 133 group B, 184 group C), but resulted in drug substitutions in only zero versus two versus four children, respectively. NNRTI plus NRTI-based three-drug or four-drug ART can be given across childhood without routine toxicity monitoring; CD4monitoring provided clinical benefit after the first year on ART, but event rates were very low and long-term survival high, suggesting ART rollout should take priority. CD4 benefits from four-drug induction were not durable, but three-NRTI long-term maintenance was immunologically and clinically similar to NNRTI-based ART and could be valuable during tuberculosis co-treatment.

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Editor’s notes: With an estimated 2 million children in need of ART in 2011 but only 28% accessing treatment, there is clearly an urgent need to scale-up access to ART. ARROW, a landmark randomised controlled trial comparing clinical to 3-monthly laboratory monitoring (CD4 count, haematology and biochemistry) has greatly added to the knowledge base about how to monitor children on ART in resource-limited settings. Firstly, ARROW demonstrates that with high-quality clinical care, excellent clinical outcomes are possible, regardless of the monitoring strategy used: with a continuous supply of ART, 1-monthly review by a nurse and 3-monthly review by a doctor, 5-year survival was remarkably high (96%) with reasonable levels of viral suppression seen in both monitoring arms (77-78% had a VL<400 copies/ml). Secondly, although rates of clinical progression were higher in the clinical monitoring arm after the second year of treatment, overall there was no morbidity / mortality benefit with routine versus clinically driven laboratory monitoring. Thirdly, as was seen in a similar trial in adults (DART), this study shows that WHO-recommended regimens can be provided safely without the need for routine monitoring for toxicity. As these excellent outcomes are unlikely to be replicated in programmatic settings, there remain uncertainties about the optimal strategy for monitoring children on ART, particularly with respect to viral load monitoring. However, the results from ARROW are very encouraging and these uncertainties should not undermine efforts to dramatically increase children’s access to ART in resource-limited settings. A commentary on the same article by Kuhn and Coovadia in the same issue of the Lancet is found here.

Africa
Uganda, Zimbabwe
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Efavirenz dose adjustments are probably not required in patients taking concurrent rifampicin

Relationship between weight, efavirenz exposure and virologic suppression in HIV-infected patients on rifampin-based TB treatment in the ACTG A5221 STRIDE study

Luetkemeyer AF, Rosenkranz SL, Lu D, Marzan F, Ive P, Hogg E, et al. Adult AIDS Clinical Trials Group A5221 Study Team. Clinical Infectious Diseases Advance Access published April 19, 2013.

Background: Rifampin (RIF) upregulates CYP 450 isoenzymes potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and HIV virologic suppression in patients on EFV (600 mg) and RIFbased TB treatment as part of a multicenter randomized trial (ACTG A5221)

Methods: EFV Cmin was measured using HPLC 20‐28 hours post‐EFV dose at weeks 4,8,16,24 on‐RIF and weeks 4,8 off‐RIF. Results evaluated with two‐sided Wilcoxon rank‐sum, chi‐square and Fisher's Exact tests and logistic regression (5% Type I error rate).

Results: 780 patients from 11 countries received EFV, 543 provided ≥ 1 EFV Cmin. Median (IQR) weight was 52.8 kg (48.0,59.5), BMI 19.4 kg/m2 (17.5,21.6), age 34 (29,41), 63% male, race Black (74%), Hispanic (20%), non‐Hispanic White (5%), Asian (1%). Median Cmin was 1.96μg/mL onRIF vs. 1.80 offRIF (p=0.067). EFV concentrations were significantly higher onRIF vs. offRIF in Blacks (2.08 vs. 1.75, p=0.005). Weight ≥60 kg onRIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs. 2.02, p=0.021). However, weight ≥60 kg was associated with more frequent HIV RNA<400 copies/mL at week 48, compared to weight <60 kg (81.9% vs. 73.8%, p=0.023).

Conclusions: Coadministration of EFV and RIFbased TB therapy was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone, which was statistically significant in Black patients. Patients weighing ≥60 kg had lower median EFV Cmin vs. those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weightbased dosing of EFV with RIF co-administration.

Abstract access 

Editor’s notes: Effective treatment of HIV-TB co-infection is complicated by drug-drug interactions. Rifampicin, the key component of effective anti-TB therapy, is a potent inducer of the cytochrome P450 enzymes which metabolize many antiretrovirals including efavirenz. Appropriate dosing of efavirenz in patients taking concomitant TB treatment has been debated, with both US and British national treatment guidelines recommending efavirenz dose increases. The WHO does not recommend adjusting dosing. This study, an analysis of efavirenz levels from 543 participants in the STRIDE study of ART timing in TB co-infected patients, suggests that efavirenz dose adjustments are not required in patients taking concurrent rifampicin based TB treatment. Efavirenz levels were not reduced in patients who were taking TB treatment. In fact trough efavirenz levels were slightly increased in patients during TB treatment. This increase in efavirenz levels was most marked in black patients. Virological outcomes with efavirenz based ART in this cohort of patients on TB treatment were good, with 76% fully suppressed at 48 weeks.  Perhaps unsurprisingly, efavirenz levels were slightly lower in patients weighing over 60 kg compared to those below 60 kg, but this did not translate into worse virological outcomes. Given the racial differences seen in efavirenz metabolism in this study there is a question about the generalisability of the study to certain populations, notably Caucasians who only made up 5% of the study population. However the demographics were representative of the vast majority of HIV-TB co-infected patients worldwide. These results strongly suggest that efavirenz at standard doses can be safely used in patients receiving rifampicin based TB treatment, avoiding the need to complicate ART treatment regimens in the large number of individuals receiving TB treatment in resource-limited public health programmes.

Avoid TB deaths
Comorbidity, HIV Treatment
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Generalized HIV epidemics require generalized prevention efforts

Extra-couple HIV transmission in sub-Saharan Africa: a mathematical modelling study of survey data.

Bellan SE, Fiorella KJ, Melesse DY, Getz WM, Williams BG, Dushoff J. Lancet. 2013 Feb 4. pii: S0140-6736(12)61960-6. doi: 10.1016/S0140-6736(12)61960-6. [Epub ahead of print]

The proportion of heterosexual HIV transmission in sub-Saharan Africa that occurs within cohabiting partnerships, compared with that in single people or extra-couple relationships, is widely debated. The proportional contribution of different routes of transmission to new HIV infections was estimated. As plans to use antiretroviral drugs as a strategy for population-level prevention progress, understanding the importance of different transmission routes is crucial to target intervention efforts. A mechanistic model of HIV transmission was built with data from Demographic and Health Surveys (DHS) for 2003-2011, of 27 201 cohabiting couples (men aged 15-59 years and women aged 15-49 years) from 18 sub-Saharan African countries with information about relationship duration, age at sexual debut, and HIV serostatus. This model was combined with estimates of HIV survival times and country-specific estimates of HIV prevalence and coverage of antiretroviral therapy (ART). The proportion of recorded infections in surveyed cohabiting couples that occurred before couple formation was estimated, between couple members, and because of extra-couple intercourse. In surveyed couples, we estimated that extra-couple transmission accounted for 27-61% of all HIV infections in men and 21-51% of all those in women, with ranges showing intercountry variation. It was estimated that in 2011, extra-couple transmission accounted for 32-65% of new incident HIV infections in men in cohabiting couples, and 10-47% of new infections in women in such couples. These findings suggest that transmission within couples occurs largely from men to women; however, the latter sex have a very high-risk period before couple formation. Because of the large contribution of extra-couple transmission to new HIV infections, interventions for HIV prevention should target the general sexually active population and not only serodiscordant couples.

Abstract access 

Editor’s notes: Understanding the individual and population level risks for HIV transmission and acquisition is essential for designing HIV transmission prevention programmes that can lead to an AIDS-free generation. The frequency of pre-marital or extra-marital sexual activity is not necessarily different in high prevalence countries than in lower prevalence settings, a number of theories have been suggested, including frequency of multiple concurrent partnerships. Newer data has indicated that a significant percentage of people living with HIV are in serodiscordant couples with HIV-negative partners – hence a focus on identification of such serodiscordancy and promotion of condom use within cohabitating serodiscordant couples. While these interventions remain important, this article highlights that quite significant proportions of HIV transmission in couples occurs outside of the framework of the cohabitating couple. HIV prevention campaigns, for persons in couples as well as single individuals must remain focused on the general sexually active population.  

Africa
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HIV infection increases mortality among HIV-positive pregnant women

The contribution of HIV to pregnancy-related mortality: a systematic review and meta-analysis.

Calvert C, Ronsmans PC. AIDS. 2013 Feb 25. [Epub ahead of print]

Whilst much is known about the contribution of HIV to adult mortality, remarkably little is known about the mortality attributable to HIV during pregnancy. In this paper the proportion of pregnancy-related deaths attributable to HIV based on empirical data was estimated from a systematic review of the strength of association between HIV and pregnancy-related mortality. Studies comparing mortality during pregnancy and the postpartum in HIV-infected and uninfected women were included. Summary estimates of the relative and attributable risks for the association between HIV and pregnancy-related mortality were calculated through meta-analyses. Varying estimates of HIV prevalence were used to predict the impact of the HIV epidemic on pregnancy-related mortality at the population level. 23 studies were included (17 from sub-Saharan Africa). Meta-analysis of the risk ratios (RR) indicated that HIV-infected women had eight times the risk of a pregnancy-related death compared with HIV-uninfected women (pooled RR: 7.74, 95% CI 5.37-11.16). The excess mortality attributable to HIV among HIV-infected pregnant and postpartum women was 994 per 100,000 pregnant women. We predict that 12% of all deaths during pregnancy and up to one year postpartum are attributable to HIV/AIDS in regions with a prevalence of HIV among pregnant women of 2%. This figure rises to 50% in regions with a prevalence of 15%.  The substantial excess of pregnancy-related mortality associated with HIV highlights the importance of integrating HIV and reproductive health services in areas of high HIV prevalence and pregnancy-related mortality.

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Editor’s notes: Millennium Development Goals include commitments to reduce maternal mortality. While HIV is a leading cause of death among women of reproductive age in sub-Saharan Africa, the contribution of HIV infection to overall maternal mortality is Africa has been less described. This analysis of this study indicates that a significant proportion of maternal deaths is due to HIV. While the contribution of HIV to maternal mortality is high in relatively low prevalence settings, it is remarkably and tragically high in high prevalence countries such as is seen in southern Africa: with an estimated 50% of maternal deaths due to HIV infection when prevalence is 15%. This modeling highlights the ongoing essential need to prevent new HIV infections if the MDGs will be met.

Epidemiology, Gender
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Getting to zero: from option B to option B+

Cost-effectiveness of World Health Organization 2010 Guidelines for Prevention of Mother-to-Child HIV Transmission in Zimbabwe.

Ciaranello AL, Perez F, Engelsmann B, Walensky RP, Mushavi A, Rusibamayila A, Keatinge J, Park JE, Maruva M, Cerda R, Wood R, Dabis F, Freedberg KA. Clin Infect Dis. 2012 Nov 30. [Epub ahead of print]

Background. In 2010, the World Health Organization (WHO) released revised guidelines for prevention of mother-to-child human immunodeficiency virus (HIV) transmission (PMTCT). We projected clinical impacts, costs, and cost-effectiveness of WHO-recommended PMTCT strategies in Zimbabwe.

Methods. We used Zimbabwean data in a validated computer model to simulate a cohort of pregnant, HIV-infected women (mean age, 24 years; mean CD4 count, 451 cells/µL; subsequent 18 months of breastfeeding). We simulated guideline-concordant care for 4 PMTCT regimens: single-dose nevirapine (sdNVP); WHO-recommended Option A, WHO-recommended Option B, and Option B+ (lifelong maternal 3-drug antiretroviral therapy regardless of CD4).

Outcomes included maternal and infant life expectancy (LE) and lifetime healthcare costs (2008 US dollars [USD]). Incremental cost-effectiveness ratios (ICERs, in USD per year of life saved [YLS]) were calculated from combined (maternal + infant) discounted costs and LE.

Results. Replacing sdNVP with Option A increased combined maternal and infant LE from 36.97 to 37.89 years and would reduce lifetime costs from $5760 to $5710 per mother-infant pair. Compared with Option A, Option B further improved LE (38.32 years), and saved money within 4 years after delivery ($5630 per mother-infant pair). Option B+ (LE, 39.04 years; lifetime cost, $6620 per mother-infant pair) improved maternal and infant health, with an ICER of $1370 per YLS compared with Option B.

Conclusions. Replacing sdNVP with Option A or Option B will improve maternal and infant outcomes and save money; Option B increases health benefits and decreases costs compared with Option A. Option B+ further improves maternal outcomes, with an ICER (compared with Option B) similar to many current HIV-related healthcare interventions.

Abstract access

Editor's notes: This very important paper tackles one of the aspects (the differential cost-effectiveness of different interventions) of the current debate around prevention of mother to child transmission. Particularly for women with CD4 cells higher than 350 (below this level, triple therapy is already the rule) progressively switching from option A (AZT/3TC plus single dose nevirapine) to option B or B+ (starting triple therapy as soon as diagnosed and continue it for life) is considered by many countries the way forward, and may soon be translated in the new WHO guidelines. Advantages of option B+ may include: a) the simplification of regimen and service delivery; b) the harmonization with ART programmes; c) the potential use of once daily, single-pill, fixed dose combinations; and d) the independence from CD4 testing for initial decision. In addition, option B+ can assure protection against MTCT in future pregnancies and may prevent sexual transmission to serodiscordant partners. Finally, it avoids the danger of stopping and starting ARV drugs and there is probably a benefit to the mother's health (because of early ART). When comparing the cost-effectiveness of the different options and looking at them in a clinical perspective, the paper suggests that the health benefit of option B+ clearly outweigh the marginal augmentation of its cost as compared with option B.

Africa
Zimbabwe
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