Kudakwashe C Takarinda

Early versus Delayed Initiation of Antiretroviral Therapy for Concurrent HIV Infection and Cryptococcal Meningitis in Sub-Saharan Africa

BACKGROUND. Cryptococcal meningitis (CM) remains a leading cause of acquired immunodeficiency syndrome-related death in sub-Saharan Africa. The timing of the initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV)-associated CM remains uncertain. The study aimed to determine the optimal timing for initiation of ART in HIV-positive individuals with CM. METHODS. A prospective, open-label, randomized clinical trial was conducted at a tertiary teaching hospital in Zimbabwe. Participants were aged > or = 18 years, were ART naive, had received a first CM diagnosis, and were randomized to receive early ART (within 72 h after CM diagnosis) or delayed ART (after 10 weeks of treatment with fluconazole alone). Participants received 800 mg of fluconazole per day. The ART regimen used was stavudine, lamivudine, and nevirapine given twice daily. The duration of follow-up was up to 3 years. The primary end point was all-cause mortality. RESULTS. Fifty-four participants were enrolled in the study (28 in the early ART arm and 26 in the delayed ART arm). The median CD4 cell count at enrollment was 37 cells/mm(3) (interquartile range, 17-69 cells/mm(3)). The 3-year mortality rate differed significantly between the early and delayed ART groups (88% vs 54%; P < .006); the overall 3-year mortality rate was 73%. The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (P = .031, by log-rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1-7.23). The study was terminated early by the data safety monitoring committee. CONCLUSIONS. In resource-limited settings where CM management may be suboptimal, when compared with a delay of 10 weeks after a CM diagnosis, early initiation of ART results in increased mortality. Trial registration. ClinicalTrials.gov identifier: NCT00830856.

Patient Retention, Clinical Outcomes and Attrition-Associated Factors of HIV-Infected Patients Enrolled in Zimbabwe's National Antiretroviral Therapy Programme, 2007???2010

Background Since establishment of Zimbabwes National Antiretroviral Therapy (ART) Programme in 2004, ART provision has expanded from <5,000 to 369,431 adults by 2011. However, patient outcomes are unexplored. Objective To determine improvement in health status, retention and factors associated with attrition among HIV-infected patients on ART. Methods A retrospective review of abstracted patient records of adults ≥15 years who initiated ART from 2007 to 2009 was done. Frequencies and medians were calculated for rates of retention in care and changes in key health status outcomes at 6, 12, 24 and 36 months respectively. Cox proportional hazards models were used to determine factors associated with attrition. Results Of the 3,919 patients, 64% were female, 86% were either WHO clinical stage III or IV. Rates of patient retention at 6, 12, 24 and 36 months were 90.7%, 78.1%, 68.8% and 64.4%, respectively. After ART initiation, median weight gains at 6, 12, and 24 months were 3, 4.5, and 5.0 kgs whilst median CD4+ cell count gains at 6, 12 and 24 months were 122, 157 and 279 cells/µL respectively. Factors associated with an increased risk of attrition included male gender (AHR 1.2; 95% CI, 1.1–1.4), baseline WHO stage IV (AHR 1.7; 95% CI, 1.1–2.6), lower baseline body weight (AHR 2.0; 95% CI, 1.4–2. 8) and accessing care from higher level healthcare facilities (AHR 3.5; 95% 1.1–11.2). Conclusions Our findings with regard to retention as well as clinical and immunological improvements following uptake of ART, are similar to what has been found in other settings. Factors influencing attrition also mirror those found in other parts of sub-Saharan Africa. These findings suggest the need to strengthen earlier diagnosis and treatment to further improve treatment outcomes. Whilst decentralisation improves ART coverage it should be coupled with strategies aimed at improving patient retention.

HIV testing uptake and retention in care of HIV-infected pregnant and breastfeeding women initiated on Option B+ in rural Zimbabwe.

Zimbabwe has started to scale up Option B+ for the prevention of mother‐to‐child transmission of HIV, but there is little published information about uptake or retention in care. This study determined the number and proportion of pregnant and lactating women in rural districts diagnosed with HIV infection and started on Option B+ along with six‐month antiretroviral treatment (ART) outcomes.

Gender-related differences in outcomes and attrition on antiretroviral treatment among an HIV-infected patient cohort in Zimbabwe: 2007-2010

SUMMARY Objectives To determine (1) gender-related differences in antiretroviral therapy (ART) outcomes, and (2) gender-specific characteristics associated with attrition. Methods This was a retrospective patient record review of 3919 HIV-infected patients aged ≥15 years who initiated ART between 2007 and 2009 in 40 randomly selected ART facilities countrywide. Results Compared to females, males had more documented active tuberculosis (12% vs. 9%; p < 0.02) and a lower median CD4 cell count (117 cells/μl vs. 143 cells/μl; p < 0.001) at ART initiation. Males had a higher risk of attrition (adjusted hazard ratio (AHR) 1.28, 95% confidence interval (CI) 1.10–1.49) and mortality (AHR 1.56, 95% CI 1.10–2.20). Factors associated with attrition for both sexes were lower baseline weight (<45 kg and 45–60 kg vs. >60 kg), initiating ART at an urban health facility, and care at central/provincial or district/mission hospitals vs. primary healthcare facilities. Conclusions Our findings show that males presented late for ART initiation compared to females. Similar to other studies, males had higher patient attrition and mortality compared to females and this may be attributed in part to late presentation for HIV treatment and care. These observations highlight the need to encourage early HIV testing and enrolment into HIV treatment and care, and eventually patient retention on ART, particularly amongst men.

Factors Associated with Ever Being HIV-Tested in Zimbabwe: An Extended Analysis of the Zimbabwe Demographic and Health Survey (2010-2011).

Introduction Zimbabwe has a high human immunodeficiency virus (HIV) burden. It is therefore important to scale up HIV-testing and counseling (HTC) as a gateway to HIV prevention, treatment and care. Objective To determine factors associated with being HIV-tested among adult men and women in Zimbabwe. Methods Secondary analysis was done using data from 7,313 women and 6,584 men who completed interviewer-administered questionnaires and provided blood specimens for HIV testing during the Zimbabwe Demographic and Health Survey (ZDHS) 2010–11. Factors associated with ever being HIV-tested were determined using multivariate logistic regression. Results HIV-testing was higher among women compared to men (61% versus 39%). HIV-infected respondents were more likely to be tested compared to those who were HIV-negative for both men [adjusted odds ratio (AOR) = 1.53; 95% confidence interval (CI) (1.27–1.84)] and women [AOR = 1.42; 95% CI (1.20–1.69)]. However, only 55% and 74% of these HIV-infected men and women respectively had ever been tested. Among women, visiting antenatal care (ANC) [AOR = 5.48, 95% CI (4.08–7.36)] was the most significant predictor of being tested whilst a novel finding for men was higher odds of testing among those reporting a sexually transmitted infection (STI) in the past 12 months [AOR = 1.86, 95%CI (1.26–2.74)]. Among men, the odds of ever being tested increased with age ≥20 years, particularly those 45–49 years [AOR = 4.21; 95% CI (2.74–6.48)] whilst for women testing was highest among those aged 25–29 years [AOR = 2.01; 95% CI (1.63–2.48)]. Other significant factors for both sexes were increasing education level, higher wealth status and currently/formerly being in union. Conclusions There remains a high proportion of undiagnosed HIV-infected persons and hence there is a need for innovative strategies aimed at increasing HIV-testing, particularly for men and in lower-income and lower-educated populations. Promotion of STI services can be an important gateway for testing more men whilst ANC still remains an important option for HIV-testing among pregnant women.

Outcomes of antiretroviral therapy among younger versus older adolescents and adults in an urban clinic, Zimbabwe.

SETTING A non-governmental organisation-supported clinic offering health services including antiretroviral therapy (ART). OBJECTIVE To compare ART retention between younger (age 10-14 years) vs. older (age 15-19 years) adolescents and younger (age 20-29 years) vs. older (age ⩾30 years) adults and determine adolescent- and adult-specific attrition-associated factors among those initiated on ART between 2010 and 2011. DESIGN Retrospective cohort study. RESULTS Of 110 (7%) adolescents and 1484 (93%) adults included in the study, no differences in retention were observed between younger vs. older adolescents at 6, 12 and 24 months. More younger adolescents were initiated with body mass index <16 kg/m(2) compared with older adolescents (64% vs. 47%; P = 0.04). There were more females (74% vs. 52%, P < 0.001) and fewer patients initiating ART with CD4 count ⩽350 cells/mm(3) (77% vs. 81%, P = 0.007) among younger vs. older adults. Younger adults demonstrated more attrition than older adults at all time-points. No attrition risk factors were observed among adolescents. Attrition-associated factors among adults included being younger, having a lower CD4 count and advanced human immunodeficiency virus disease at initiation, and initiation on a stavudine-based regimen. CONCLUSION Younger adults demonstrated greater attrition and may require more attention. We were unable to demonstrate differences in attrition among younger vs. older adolescents. Loss to follow-up was the main reason for attrition across all age groups. Overall, earlier presentation for ART care appears important for improved ART retention among adults.

Communicable and non-communicable diseases: connections, synergies and benefits of integrating care.

There is a growing association between communicable and non-communicable diseases in low- and high-income countries and amongst the rich and the poor. In low- and middle-income countries especially, adults continue to be plagued by communicable diseases such as human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) and tuberculosis (TB), while at the same time being increasingly threatened by non-communicable diseases such as cardiovascular disease and diabetes mellitus (DM). Recent global data show that every year about 1.1 million people die from TB, 1.5 million people die from HIV/AIDS, nearly 5 million die from DM and over 9 million die from hypertension-related disease. Most of this mortality is premature.1 Reducing these deaths on a global scale will require not only the implementation of specific treatments for each disease but also the recognition that there are important interactions between different diseases and useful synergies and benefits that can be gained from exploiting overlapping treatments and strategies. For example, there is a strong association between HIV and TB. HIV exacerbates the risk of TB, including recurrent disease, and increases morbidity and mortality in those with TB, while TB is one of the most important opportunistic infections and the cause of death in many persons living with HIV (PLHIV). The most important strategy for preventing TB in PLHIV is antiretroviral therapy (ART),2 and the impact of this intervention can be strengthened by the implementation of the ‘Three Is’ (intensified TB case finding, isoniazid preventive therapy and infection control). ART is also the most important strategy for reducing mortality in HIV-infected patients with TB, with its impact strengthened by concomitant use of cotrimoxazole and attention to the prevention, diagnosis and treatment of other opportunistic infections.3 Maximising the benefits of these interventions requires expanded coverage and scale-up of quality-assured HIV testing to reach as many PLHIV and patients with TB as possible, especially those from vulnerable and marginalised groups; this activity is recognised in the UNAIDS recent 90-90-90 strategy.4 At the same time, PLHIV are also at increased risk of premature cardiovascular disease due to a higher prevalence of traditional risk factors such as smoking, alcohol and substance abuse, adverse effects of certain antiretroviral (ARV) drugs such as abacavir and some protease inhibitors and the direct effects of HIV itself. In HIV-infected persons, whether they are on ART or not, there is chronic activation of the innate immune system with excessive production of inflammatory markers that in turn are associated with an increased risk of atherosclerosis, coronary artery inflammation and all-cause mortality.5 Markers of hypercoagulation are increased, and these are associated with systemic clotting, tissue damage and disease progression.5 HIV-mediated breakdown of the integrity of the gut mucosa and chronic translocation of gut microbial products into the systemic circulation all contribute to this chronic inflammatory state. Angiotensin converting enzyme (ACE) inhibitors and HMG-CoA reductase inhibitors (‘statins’) reduce cardiovascular risk through their anti-hypertensive and cholesterol-lowering properties, respectively, but both classes of drug also appear to have anti-inflammatory effects that may be especially beneficial for persons with HIV.5 Smoking and hypertension are two important risk factors for cardiovascular and other non-communicable diseases for which it is potentially easy to screen, and they deserve far more attention than is currently the case in busy ART clinics in low- and middle-income countries. There is convincing evidence, for example, in Europe and North America, that smoking reduces the life expectancy in PLHIV on ART,6 which suggests that smoking cessation interventions could have an important impact in improving longer-term outcomes. In a North American cohort of PLHIV, attention to lipid-lowering and anti-hypertension therapy combined with more lipid-friendly and less toxic ARV drugs has been shown to significantly reduce the risk of myocardial infarction,7 suggesting the importance of including such interventions in the care package of PLHIV. In another example, there are important associations between DM and TB. DM, both type 1 and type 2, increases the risk of TB by a factor of two or three, and 2012 estimates put the number of adult TB cases associated with DM at just over one million.8 Persons with dual disease have worse TB treatment outcomes, with delayed sputum culture conversion and an increased risk of death, treatment failure or recurrent TB after successful treatment completion.9,10 Conversely, TB, like other infections, can worsen blood glucose control and complicate the clinical management of DM. Bi-directional screening and integrated management should help to improve early diagnosis, treatment and health outcomes of both conditions. This was recommended in 2011 when the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (The Union) launched the Collaborative Framework for Care and Control of Tuberculosis and Diabetes to guide policy makers and implementers in moving forward to combat the epidemic of TB and DM.11 Some modifications are needed when treating DM in TB patients: sulphonylurea derivatives are best avoided in treating patients with dual disease because of their interaction with rifampicin, leaving insulin and metformin as suitable alternatives. There is preliminary evidence to suggest that metformin in its own right is a promising host-adjunctive therapy for TB, with studies showing in vitro action against Mycobacterium tuberculosis and in vivo activity in controlling tuberculous infection and modifying disease severity.12 The comorbidities associated with the communicable diseases of HIV/AIDS and TB and their links with non-communicable diseases are emerging research priorities.13 However, more needs to be done at the implementation level to integrate care and treatment. The oft-quoted comments that TB and ART clinics are too busy to take on the additional tasks around non-communicable diseases or that clinics for non-communicable diseases do not understand or want to take on public health screening for infectious diseases must be acknowledged. However, maintaining the status quo will not help reduce the huge burden of premature mortality or unlock the potential improvements in outcomes of integrated care. Operational research or implementation science would help to pave the way forward by testing whether, for example, screening all PLHIV or TB patients for blood pressure or fasting blood glucose, respectively, is feasible and cost-effective or whether such screening should be targeted at certain individuals based on age, body mass index or smoking status. Depending on context, other non-communicable diseases such as cervical cancer, renal disease and mental illness could also be considered. To date, direct evidence of the benefits of integrated services remains scarce and this needs to change.14 Communicable and non-communicable diseases occur within the same patient populations, and it is vital to secure the necessary political and programmatic commitment for integrated, effective and sustainable action to address them. This in turn will help achieve the goal of healthy lives and wellbeing for all.

Follow-up and programmatic outcomes of HIV-exposed infants registered in a large HIV centre in Lilongwe, Malawi: 2012 - 2014.

To assess follow‐up and programmatic outcomes of HIV‐exposed infants at Martin Preuss Centre, Lilongwe, from 2012 to 2014.

Management and treatment outcomes of patients enrolled in MDR-TB treatment in Viet Nam

SETTING The programmatic management of drug-resistant tuberculosis (TB) in Viet Nam has been rapidly scaled up since 2009. OBJECTIVES To document the annual numbers of patients enrolled for multidrug-resistant tuberculosis (MDR-TB) treatment during 2010-2014 and to determine characteristics and treatment outcomes of patients initiating treatment during 2010-2012. DESIGN A retrospective cohort study using national reports and data from the national electronic data system for drug-resistant TB. RESULTS The number of patients enrolled annually for MDR-TB treatment increased from 97 in 2010 to 1522 in 2014. The majority of patients were middle-aged men who had pulmonary disease and had failed a retreatment regimen; 77% had received ⩾2 courses of TB treatment. Favourable outcomes (cured and treatment completed) were attained in 73% of patients. Unfavourable outcomes included loss to follow-up (12.5%), death (8%) and failure (6.3%). Having had ⩾2 previous treatment courses and being human immunodeficiency virus-positive were associated with unfavourable outcomes. CONCLUSION Increasing numbers of patients are being treated for MDR-TB each year with good treatment outcomes under national programme management in Viet Nam. However, there is a need to increase case detection-currently at 30% of the estimated 5100 MDR-TB cases per year, reduce adverse outcomes and improve monitoring and evaluation.

Ending the HIV/AIDS epidemic in low- and middle-income countries by 2030: is it possible?

The international community has committed to ending the epidemics of HIV/AIDS, tuberculosis, malaria, and neglected tropical infections by 2030, and this bold stance deserves universal support. In this paper, we discuss whether this ambitious goal is achievable for HIV/AIDS and what is needed to further accelerate progress. The joint United Nations Program on HIV/AIDS (UNAIDS) 90-90-90 targets and the related strategy are built upon currently available health technologies that can diagnose HIV infection and suppress viral replication in all people with HIV. Nonetheless, there is much work to be done in ensuring equitable access to these HIV services for key populations and those who remain outside the rims of the traditional health services. Identifying a cure and a preventive vaccine would further help accelerate progress in ending the epidemic. Other disease control programmes could learn from the response to the HIV/AIDS epidemic.