Special Article Management of TB/HIV co-infection: the state of the evidence Kwasi Torpey1,2, Adwoa Agyei-Nkansah* 2, Lily Ogyiri1, Audrey Forson2, Margaret Lartey2, William Ampofo3, Joseph Akamah2 and Peter Puplampu2 Ghana Med J 2020; 54(3): 186-196 doi: http://dx.doi.org/10.4314/gmj.v54i3.10 1Department of Population, Family and Reproductive Health, University of Ghana School of Public Health 2Department of Medicine and Therapeutics, University of Ghana Medical School 3Department of Virology, University of Ghana Noguchi Memorial Institute of Medical Research Corresponding author: Adwoa Agyei-Nkansah E-mail: afrakomaagyei@yahoo.com Conflict of interest: None declared SUMMARY Tuberculosis (TB) and HIV are strongly linked. There is a 19 times increased risk of developing active TB in people living with HIV than in HIV-negative people with Sub-Saharan Africa being the hardest hit region. According to the WHO, 1.3 million people died from TB, and an additional 300,000 TB-related deaths among people living with HIV. Although some progress has been made in reducing TB-related deaths among people living with HIV due to the evolution of diagnostics, treatment and antiretroviral HIV treatment, multi drug resistant TB is becoming a source of worry. Though significant progress has been made at the national level, understanding the state of the evidence and the challenges will better inform the national response of the opportunities for improved patient outcomes. Keywords: Tuberculosis, management, HIV, MDR TB, Ghana Funding: None INTRODUCTION Tuberculosis (TB) is among the leading causes of mor- Consequently, the goals of the Stop TB Partnership tality worldwide (ahead of human immunodeficiency vi- (which precedes the End TB Strategy) coined out of the rus, (HIV) from infectious diseases. In 2017, tuberculosis MDG target six were also met.5 The milestones of the resulted in 1.6 million deaths globally. Although its mor- End TB Strategy are to reduce the absolute number of TB tality fell by 37% from 2000 to 2016.1,2,3 deaths by 35% and 75% by 2020 and 2025 respectively and to achieve a decline in TB incidence rate by 20% and Tuberculosis ranks ninth among the leading causes of 50% respectively by 2020 and 2025.6 Currently, the diseases globally. The incidence of TB in 2017 was 10.0 global mortality rate (among HIV-negative people) de- million, with almost two-thirds occurring in just eight clines by 3% yearly whiles the incidence rate reduces by countries (China, Philippines, Pakistan, Nigeria, South 2% yearly.2 In order to meet the 2020 milestones, the de- Africa, Bangladesh, Indonesia and India).2 Fifty-four cline in the incidence rate and mortality should be 4 – 5 million deaths have been prevented between the year % and 10% every year respectively.2 Globally, sub-Sa- 2000 and 2017 because of improved diagnosis and effec- haran Africa (SSA) region is an area with high TB/HIV tive management of TB worldwide. The WHO European associated deaths and morbidity. SSA has 12% of the and African regions have experienced the most rapid de- world’s population but accounted for 30% of the 9 mil- clines in mortality; 5% and 4% respectively from 2013 to lion TB cases and over 250 thousand TB-related deaths. 2017. The End TB Strategy is one of the time-specific Coupled with this, is the high prevalence of HIV in this strategies that set targets for prevention, care, and control region leading to 50% of these patients being co-infected of TB. The WHO declaration of TB as a global public with HIV.7 health emergency in 1993 led to these high-level inter- ventions. The world has experienced a gradual improve- In 2016, the WHO African region contributed to 25% of ment of the situation ever since.4 In 2015, the WHO pro- the total number of incident cases of both TB mono in- claimed to have accomplished the goals set in target six fection and TB/HIV dual infection globally. Nigeria re- of the Millennium Development Goals (MDGs) which ported 407 cases per 100,000 population in that same aimed to halt and reverse TB incidence. year contributing to 8% of the global incidence compared to 322 cases per 100,000 in the previous year.8 186 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article This may, however, be an underestimation because only HIV infection was discovered in the early 1980s.15 15% of TB cases were notified in 2015.8 Among HIV in- About 77.3 million people globally have had the infec- fected persons, TB is the leading cause of death, espe- tion with 35.4 million deaths since its discovery. Preven- cially in resource-limited settings like Africa. Several tion strategies have helped to decrease the incidence of factors have been attributed to the high prevalence of TB HIV infection by nearly half (47%) since 1996. Also, the in Africa including HIV, some environmental and social uptake and scale-up of highly active antiretroviral drugs factors like poverty and poor nutrition.9 (HAART) have contributed to the decline in AIDS-re- lated deaths by 51% since 2004. In 2017, 36.9 million Contributing to the burden of this disease is the emer- people worldwide were estimated to be living with gence of Multi-Drug Resistant TB (MDR-TB),10,11 HIV.16 caused by Mycobacterium tuberculosis (M.tb) strains re- sistant to at least rifampicin and isoniazid; and of Exten- HIV infection spread rapidly since the first case was di- sively Drug-Resistant TB (XDR-TB). XDR-TB organ- agnosed in Ghana in 1986.17 The trend of new infections isms are resistant to rifampicin, isoniazid, plus any fluo- since year 2000 has decreased steadily from 30,000 to roquinolone and at least one of the three injectable sec- 20,000 in 2016. Death rates have also taken a similar path ond-line TB drugs (amikacin, kanamycin, capreomycin). from about 30,000 to 15,000 between 2000 and 2016.18 Weaknesses in health systems, lack of resources and in- About 310,000 adults and children are living with the in- effective treatment regimens coupled with other opera- fection in the country, of which 130,000 are estimated to tional treatment challenges all contribute to the low cure be on antiretroviral therapy (ART). The estimated adult rates. (15 to 49 years) prevalence is about 1.7%.15 HIV/AIDS has orphaned about 270,000 children 17 years or younger The national TB prevalence survey concluded in 2014, in the country. Among the regions, the Volta and Brong- reported a TB incidence 165/100,000 population in the Ahafo Regions recorded the highest prevalence of 2.7% country. The latest report shows a decline in the inci- whilst the Northern Region had the lowest (0.7%).14 The dence of TB in Ghana (156/100,000 population) since proportion of HIV subtype 1 in Ghana is 98.5%, and that 2014.7 On the contrary, mortality among HIV-negative of dual infections of HIV subtypes 1 and 2 is 1.5%.19 TB patients remains the same (36/100,000 populations Ten percent of the 10.4 million TB patients worldwide from 2014 to 2016) and that among HIV-positive TB pa- also had HIV infection.20 About 74% of co-infected per- tients has rather increased from 16 to 20 deaths per sons live in SSA. About 390,000 and 374,000 deaths oc- 100,000 population in the same period.12,13 curred as a result of the co-infection globally in 2015 and 2016 respectively.7 National TB case notification rates have declined from about 62/100,000 population in 2008 to 54/100,000 pop- HIV co-infection increases one’s risk of developing ac- ulation in 2016. A similar trend is occurring at the re- tive TB by about 19 times compared to HIV mono-infec- gional levels. The Greater Accra, Western, Eastern and tion. Co-infected patients are more susceptible to multi- Volta Regions recorded the highest case-notification drug-resistant or extensively drug-resistant TB.20 Testing rates in 2016, higher than the average figure for the whole of all TB and HIV- positive patients for the dual infection country, whiles the Northern Region recorded the lowest and timely initiation of therapy are essential in reducing rate 24/100,000 population. The rate for Upper West is mortality and the burden of TB/HIV co-infection.7 48/100,000.14 The treatment coverage of tuberculosis in Ghana reached The first pillar of the End TB Strategy, which is “Inte- 100% in the year 2000.21 Much effort had been put into grated, patient-centred care and prevention” has four key active and passive case finding of TB and subsequent components. These are the early diagnosis of TB, includ- linkage to care. The incidence of the dual infection in ing universal drug susceptibility testing, and systematic 2016 was 35/100,000 population; a reduction from screening of contacts and high-risk groups; treatment of 42/100,000 population in two years.12,13 Nearly a quarter all people with TB, including drug resistant TB, and pa- of roughly 15,000 TB cases notified with known HIV sta- tient support; collaborative TB/HIV activities and man- tus tested positive in the three years preceding 2017, with agement of comorbidities; and preventive treatment of 1,200 (39 – 43%) of them receiving ART.12,13,22 The esti- persons at high risk and vaccination against TB. Reduc- mated proportion of TB/HIV patients in Ghana receiving tion in TB incidence and mortality require widespread ac- ART is less than 25%.3 As pertains in other Sub-Saharan cess to diagnosis and care and treatment to substantially African countries, the effect of HIV on TB has led to lower the risk of developing TB in people who have a challenges in the control of the infection. Ghana is clas- latent TB. Ghana is one of the countries that has imple- sified as a country with a high burden. mented this in her policy. 187 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article Hospital studies have also shown that the prevalence of It is recommended that two consecutive sputum speci- HIV in TB patients is approximately 25–30% and that as mens of an individual must undergo smear microscopy to many as 50% of patients with chronic cough could be identify smear-positive patients correctly. Sputum smear HIV positive.23 microscopy is the core method for diagnosing smears positive pulmonary TB in Ghana. It is usually preceded We present in this paper, the state of the art in TB/HIV by clinical screening and a chest x-ray. CD4 counts when dual infection management, taking into consideration the available can help clinicians interpret presentation more evolution of diagnostics, treatment, and their accompa- accurately, as non-classic presentations may accompany nying challenges. It highlights the situation in Ghana and lower CD4 counts.23 Over-reliance on sputum smear mi- opportunities for management of TB-HIV for improved croscopy which is a low-sensitivity visual diagnostic test patient outcomes. that cannot determine drug resistance has side-lined indi- viduals whose illnesses are characterised by a lower TB METHODS bacillary load, such as children and individuals with HIV We searched for full-text articles published from 2000 to and diabetes, and also those with extrapulmonary or 29 2018 from three bibliographic databases, namely Pub- drug-resistant tuberculosis. Med, ScienceDirect and Google Scholar. The keywords used as search terms were TB, HIV, diagnosis, treatment, Culture Ghana, Africa. Published studies and treatment guide- Compared to microscopy, culture has a higher sensitivity lines on the diagnosis, management and treatment of and it is capable of differentiating tuberculous from non- TB/HIV co-infection were selected for inclusion. Only tuberculous mycobacteria, although it takes relatively peer-reviewed articles published in English were se- longer to have test results and is more expensive to carry out.25lected. RESULTS The conventional use of culture has been performed on solid media until the invention of liquid media systems Diagnostics which used radioactive growth indicators and later the Microscopy fast, efficient and sensitive fluorometric assays. Liquid Sputum smear microscopy is one of the traditional diag- media is relatively more sensitive and yields results faster nostic methods for detecting the presence of mycobacte- in a matter of days compared to solid media which takes ria tuberculosis complex species (MTBC). The presence about 4 to 6 weeks.30 It can be used to perform drug sus- of the thick cell walls of MTBC is stained by acidic rea- ceptibility testing (DST), making it the preferred method, gents used in the Ziehl-Neelsen method, which gives especially in high-income countries.31 One disadvantage them the ‘acid-fast’ characteristic and can be identified of liquid culture is that it can be easily contaminated, under a light microscope. The method of staining was hence affecting results. Culture-based methods remain first used by Robert Koch and later led to the discovery the gold standard for diagnosing TB and for DST, even of Mycobacteria tuberculosis in 1882.24 The tests can be in the advent of rapid molecular tests.32 It is used in addi- performed at peripheral and high-level laboratories and tion to sputum smear microscopy in making final clinical are cheap to operate.25 judgement.23 The light-emitting diode (LED) fluorescent microscope GeneXpert is an innovation that simplifies viewing of fluorescent The increasing incidence and case-fatality rates of both acid-fast bacilli (AFB) stains that were previously diffi- MDR-TB and TB/HIV necessitated the need for diagnos- cult to do so due to handling methods required.26 LED tic methods that are quick, easy to perform and afforda- microscope replaced conventional microscopy (per 2010 ble, especially for resource-constrained areas. In 2004, WHO recommendations) as the preferred tool for carry- 27 the GeneXpert system was established, and it brought ing out sputum smear microscopy. The added ad- about novel ways of performing polymerase chain reac- vantage of using fluorescence is the increased specificity 26 tion (PCR) based tests by simplifying and automating all (10% higher) compared to light microscopy. Previ- the processes in performing the test. The Xpert® ously, three specimens were collected at different times MTB/RIF assay was finally completed in 2009 and made of the day for examinations. However, studies showed it possible to perform molecular tests without the need for that ‘spot’ collections of two specimens were enough to standard laboratory settings. The Xpert® MTB/RIF assay make a confident diagnosis since a third specimen does is a nucleic acid amplification test (NAAT) that can be little to increase the specificity of the test.28 performed directly on sputum and a few extrapulmonary specimens such as cerebrospinal fluid.33 188 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article The first time it was recommended by the WHO was in WHO. They can detect resistance to rifampicin and iso- 2010 and subsequently in a policy update published in niazid, with results being ready in up to 48 hours.40 The 2013. The updated guidelines gave recommendations on second-line line probe assay (SL-LPA) was introduced to the use of Xpert® MTB/RIF to diagnose TB in children, test for resistance to second-line injectable drugs and pulmonary TB (PTB), extrapulmonary TB (EPTB), fluoroquinolones after RR-TB or MDR-TB have been di- multi-drug resistant TB (MDR-TB) and TB among per- agnosed. This development was expedient since the pre- sons with HIV.31,34, The technology can be used to diag- scription of the shorter standardised MDR-TB regimen nose TB and identify rifampicin-resistance (RR) in no requires the exclusion of resistance to second-line regi- more than two hours. It has demonstrated to have a higher men before initiation, as recommended in the WHO sensitivity for smear-negative culture-positive TB, guidelines for drug-resistant TB (DR-TB). hence, useful in detecting TB among persons with HIV. The technology can be used at low levels of the labora- After having these tests done, the clinician can determine tory network since its biosafety requirements are compa- the appropriate treatment regimen for patients to optimise rable to that of smear microscopy.33 outcomes without having to resort to trial and error. The SL-LPA is recommended in place of phenotypic DST as Useful as it is, however, it does not replace the need for the initial test after establishing MDR-TB or RR-TB. One microscopy, culture and DST in monitoring treatment limitation of the test that requires more scientific enquiry and detecting resistance to anti-TB agents apart from ri- is that though the test can identify mutations in the genes, fampicin.31 More recently, the WHO has issued a recom- they may not mean that the MTBC strain is resistance to mendation that the GeneXpert Ultra can be used in place all drugs that fall under a particular group. of GeneXpert MTB/RIF in all settings. We are yet to fully understand the different levels of re- The Xpert Ultra showed better performance in detecting sistance or cross-resistance that exist.41 Another limita- TB in difficult-to-diagnose populations like persons liv- tion is they can only be performed in laboratories that ing with HIV, children and in extrapulmonary TB. The rank high in the network, like central or national refer- sensitivity was up to 17% higher.35 There has been a 45% ence laboratories.42 surge in case detection in patients infected with HIV with the introduction of the Xpert MTB/RIF test, which has a Lipoarabinomannan assay (LAM) greater sensitivity than sputum smear microscopy thus TB diagnosis among HIV positive patients can be chal- resulting in significant strides made not only in TB diag- lenging. Sputum microscopy and the classical radiologi- nosis but also in the detection of isoniazid and rifampicin cal signs are often not the case. Also, HIV-TB coinfected resistance cases.36,37 may present with extrapulmonary symptoms. 43 The lat- eral flow lipoarabinomannan (LF-LAM) assay with a The introduction of GeneXpert as a TB diagnostic test higher sensitivity even in severely compromised HIV pa- has led to many countries modifying their TB policy im- tients. It detects the presence of lipoarabinomannan plementation strategies. South Africa, Swaziland, Brazil (LAM) antigen in urine which is present in people with and Moldova use GeneXpert MTB/RIF as the initial di- active TB.44,45 The test is relatively easy to perform, agnostic test for all suspected cases whilst countries like cheap and needs little biosafety protocols as the risk of the Philippines uses the GeneXpert MTB/RIF test fol- infection from the collection of sample is low compared lowing an abnormal digital chest X-ray and smear-nega- to sputum smear microscopy. tive sputum on microscopy.38,39 The application of LF-LAM could improve early detec- It has been documented that the GeneXpert MTB/RIF as- tion of TB in people living with HIV and prevent delays say test increases in TB cases detected given its higher in the initiation of anti-TB treatment. The WHO recom- sensitivity compared to microscopy; thus, it increases the mends the use of LF-LAM to help diagnose TB only numbers of bacteriologically positive cases. There is also among persons with HIV infection with CD4 count less an increased detection of Rifampicin-resistant TB than 100 cells/mm3 who are seriously ill or persons with cases.39. Due to its short turnaround time, Gene Xpert HIV who are seriously ill irrespective of CD4 cell count. MTB/RIF tests reduce diagnostic delay and time to treat- The recommendation also suggests using the test in chil- ment initiation, thus reducing morbidity and mortality as- dren, although there are concerns about its specificity sociated with TB disease. Overall the test is said to be among children. The use of other diagnostic tests like cost-effective especially in high burden settings.38,39 Xpert MTB/RIF, culture or sputum smear microscopy is encouraged since they exceed the LF-LAM in diagnostic Line Probe Assay accuracy in general.46 The line probe assay (LPA) (which also uses molecular tests) was recommended for the first time in 2008 by the 189 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article Tuberculosis Screening and Diagnosis Protocol in Ghana Until recently, presumptive pulmonary TB diagnosis was mainly by sputum smear microscopy in Ghana. This is readily available and has widespread use in most govern- ment health facilities in the country. TB is considered as a disease of public health interest; the cost of diagnosis and treatment is free to all patients. Currently, the Gen- eXpert MTB/RIF assay test is the recommended first-line in Ghana. With the introduction of GeneXpert MTB/RIF assay test, screening for any presumptive TB cases is first by a dig- ital X-ray and later with GeneXpert MTB/RIF if indi- cated. This has led to fewer laboratory request for TB cases as compared to the era where Smear Microscopy was used as the screening and diagnostic tool in Ghana. Figure 2 Algorithm for screening and diagnosis TB for facility-based case finding in Ghana (Source NTP,2018). Figure 1 Algorithm for screening and diagnosis TB in people living with HIV in Ghana (Source NTP,2018). Figure 3 Algorithm for screening and diagnosis TB for Community Targeted screening in Ghana (Source NTP, 2018) 190 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article DISCUSSION Later in 2006, guidelines for national programmes of re- Clinical Management source-limited settings were developed. For people living TB preventive therapy in malaria endemic regions, a threshold CD4 count of < The WHO defines latent TB infection as: “a state of per- 350 cells/mm3 was indicative of cotrimoxazole preven- sistent immune response to stimulation by Mycobacte- tive therapy for adults and adolescents to prevent malaria rium tuberculosis without evidence of clinically mani- and other bacterial infections. It was also recommended fested active TB”. It is estimated that about one-third of for persons with WHO stages three or four of HIV infec- the world’s population has latent TB infection. The pro- tion and also persons with extrapulmonary TB.53 Cur- gression of latent infection to active disease is influenced rently, WHO recommends that cotrimoxazole preventive by factors such as immunosuppression (which may therapy be given to all TB/HIV patients as soon as possi- sometimes be caused by HIV infection) and malnutrition. ble and throughout anti-TB treatment. The prophylaxis is given to prevent the breakout of opportunistic infections Latent infection, when detected, can be treated with iso- that are common among persons living with HIV and is niazid to prevent the development of active TB disease. encouraged among people with TB/HIV co-infection in Isoniazid preventive therapy (IPT) is recommended for combination with ART where it gives continual protec- HIV-positive persons and children under five years who tion against bacterial infections, diarrhoea and malaria in have household contact with bacteriologically confirmed Africa.54 TB patients. Though isoniazid preventive therapy is strongly recommended as part of the basic HIV care Timing of ART initiation in co-management of package, it is poorly implemented in several countries.47 TB/HIV Poor implementation can be attributed to issues of the CD4 cell count played an important role in the care and supply chain, challenges excluding active TB, financing management of opportunistic infections in HIV/AIDS. of drug costs, unfounded concerns about isoniazid among Until recently, CD4 cells was used in determining the in- others.48,49 itiation of ART. This was when drug toxicity, affordabil- ity and availability were major issues of concern in the Implementation of isoniazid prophylaxis as part of the late 1990s.55 In 2002, the CD4 threshold for starting ART HIV-TB response is extremely low. Actual coverage of was less than 250 cells/mm3.56 The drug combinations IPT among HIV infected persons in Ghana is lacking.12 used then had high pill burden, less effective and associ- It is expected that HIV infected infants who are less than ated with high risk of toxicity and resistance. one year with or without household contact of active TB patients receive isoniazid for six months as long as they With time, more effective, less toxic, and affordable are declared to be without active TB disease. Monother- combinations were developed which paved way for re- apy of isoniazid lasting six months is recommended for search into the optimal CD4 threshold to initiate ART. the treatment of LTBI in adults and children. Other alter- More studies reported the advantages of initiating ART natives include daily isoniazid and rifampicin for three at higher CD4 thresholds and they began to reflect in the months for children and adolescents less than fifteen 2010 WHO guidelines, where the threshold was raised to years. Rifapentine and isoniazid may also be given 350 cells/mm3, then to 500 cells/mm3 in 2013.55 Recent weekly for three months for adults and adolescents.50 studies show that starting ART among persons with CD4 above 500 cells/mm3 is beneficial and even reduces the Cotrimoxazole preventive therapy risk of transmission to other persons.57 The latest WHO The WHO provisionally recommended the use of fixed- guidelines, therefore, recommend early initiation of dose combination of trimethoprim-sulphamethoxazole ART, hence treating all patients, irrespective of CD4 (cotrimoxazole) for preventive therapy in people living count, and as soon as a confirmed diagnosis of HIV in- with HIV in Africa in the year 2000. The prophylaxis was fection is made.54 to be given to asymptomatic adults with CD4 counts less than 500 cells/mm3, symptomatic individuals at stage two Nevertheless, a baseline CD4 count is required to deter- of HIV disease or higher and pregnant women in second mine the stage of the disease. The use of viral load tests or third trimesters. Cotrimoxazole was also recom- is preferred in monitoring disease progression and re- mended for infants six weeks or older exposed or proven sponse to treatment.55 A clinical trial conducted in Cote to be infected with the virus.51 These recommendations D’Ivoire showed the benefit of co-treatment with ART came a year after a randomised trial conducted in Cote and IPT on reducing TB events among persons with HIV. D’Ivoire reported a decline in mortality of 48% among However, the change in CD4 counts did not differ signif- people living with HIV who received cotrimoxazole icantly between patients who were given IPT and those prophylaxis compared to those who received placebo.52 who were not. 191 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article The study showed that early initiation of ART and six TB-HIV in children months of IPT given concomitantly was safe and that this The diagnosis of PTB in children is difficult, more so in therapy reduced the risk of tuberculosis events and other HIV associated PTB. The presence of other pulmonary HIV-related comorbidities by 44 % and mortality by all diseases related to HIV infection, atypical chest x-ray causes by 35% compared to administration of ART findings and young age (1 to 5 years) are just few of sev- alone.58 The third edition of the WHO treatment guide- eral factors that make detection of TB difficult.59 The di- lines for TB, which was published in the year 2003 gave agnosis and treatment of TB is same for all children irre- four possible options for the timing of ART initiation for spective of HIV status. The regimen is also same for TB/HIV co-infected patients. adults, however, dose adjustment is made based on body weight.62 The options included: • initiating ART after the full course of anti-TB As in adults, the recommendation is to treat all children treatment was completed, with HIV regardless of CD4 count. The timing of ART • initiating ART after the initial phase of anti-TB in HIV associated TB is like that recommended for treatment was completed, and giving ethambu- adults. For children with CD4 less than 50 cells/mm3 tol and isoniazid in the continuation phase, ART must be started within two weeks of anti-TB. Cotri- • using a rifampicin-based regimen in addition to moxazole preventive therapy is also recommended as two nucleoside reverse transcriptase inhibitors part of integrative therapy of TB/HIV management in (NRTIs) or children.63 • using a rifampicin-based regimen in addition to two NRTIs, then upon completion of anti-TB Management of PTB and EPTB (TB meningitis) treatment, change ART regimen to a maximally Anti-TB regimen given to HIV-positive patients is same suppressive HAART.59 for HIV-negative patients. Thioacetazone used in the 1990s was replaced with ethambutol because of severe Anti-TB treatment is prioritised over ART in order to adverse reactions on the skin, which was sometimes fatal stop transmission of TB (especially in the case of smear- in HIV patients.27,59,63 positive PTB), however, there is a need to treat both TB and HIV concurrently in order to maximise survival ben- Treatment of TB is in two phases: the initial/intensive efit. Patients with disseminated TB or with CD4 counts phase where a combination of four medications are less than 200/mm3 were eligible for concurrent initiation given, lasting for two or three months for first and sec- of both ART and anti-TB medications back in 2004, ond-line treatment, respectively. The goal of the inten- whilst those who showed no signs of serious illness had sive phase is to greatly reduce the bacterial burden and to defer ART until after the initial phase of anti-TB treat- render the patient non-infectious. The continuation phase ment.60 (combinations of two drugs are used), which also lasts for four to six months, depending on the regimen given aims Early initiation of ART reduces mortality among at sterilising or clearing the patient of the mycobacteria. TB/HIV co-infected patients, 60,61 informing later recom- This is known as the short-course therapy.27 mendations of the WHO on starting ART for all HIV pos- itive patients regardless of CD4 cell count as soon as pos- The main drugs used in the treatment of TB include iso- sible or within the first eight weeks of beginning anti-TB niazid (H), rifampicin (R), pyrazinamide (Z), and etham- regimen. The timing of ART initiation in this instance is butol (E) and streptomycin (S) (no longer a key part of very crucial to the survival of people with dual infection short-course therapy). The earlier versions of the treat- since deaths have been shown to occur mostly within the ment guidelines recommended an intensive phase of two first two months or during the intensive phase of anti-TB months’ daily dose or an intermittent dose of HRZE/ treatment. The latest guidelines, however, stress on start- HRZS and six months of HE or four months of HR de- ing ART within the first two weeks of anti-TB treatment pending on the formulation chosen by the respective na- for patients with CD4 counts less than 50 cells/mm3 and tional program and resources available in the country. It within eight weeks for persons with higher CD4 counts.54 was thought at that time that intermittent intake (three The exact timing of ART for TB and HIV co-treatment times weekly) was as efficacious as daily intake.59,63 still remains unclear, as clinicians deal with adverse re- actions, adherence, immune reconstitution and other A systematic review by Khan et al., showed that intermit- problems that are associated with it. tent intake was associated with higher rates of treatment failure or relapse compared to daily dosing.64 The WHO in their 2010 publication of treatment guidelines there- fore recommended daily intake of drugs.27 192 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article Furthermore, new patients who test positive for sputum line anti-TB regimen and who have no resistance to fluo- smear examination at the end of the intensive phase can roquinolones and second-line injectable drugs.66 now move to the continuation phase without extending the intensive phase (as was the standard previously) as With regards to the timing of ART during treatment of long as treatment regimen contains rifampicin.3,27 MDR-TB, some questions remain unanswered. Early guidelines suggested initiating ART at two weeks of anti- HIV infected patients often present with extrapulmonary TB treatment for individuals with CD4 less than 200 TB signifying an advanced disease. HIV-associated ex- cells/mm3 and eight weeks for those with CD4 between trapulmonary TB is classified as WHO clinical stage four 200 and 350 cells/mm3. of HIV infection (AIDS). It may present as disseminated TB, TB associated pericarditis, lymphadenitis, meningi- WHO treatment guidelines for drug-resistant tis, among others. The diagnosis of extrapulmonary TB tuberculosis recommend ART for all HIV positive MDR- can be challenging and often require experienced physi- TB cases irrespective of CD4 count between two and cians to make accurate diagnosis as suggested in the Gha- eight weeks (as early as possible) of starting anti-TB reg- naian TB management and care guidelines.23 imen, though the quality of evidence for this recommen- dation is low.65,66 The optimal timing of ART for HIV The management of extrapulmonary TB is essentially the associated MDR-TB is still unknown. The concerns are same as that of pulmonary TB, although the duration of quite different in patients who are diagnosed with drug- treatment may be prolonged for up to nine to twelve resistant TB (DR-TB) while on ART. If ART failure is months in the former.27 The use of adjuvant corticoster- detected to be the cause of TB disease, the ART regimen oids such as dexamethasone or prednisolone for six to is changed to second-line between two to eight weeks af- eight weeks for persons with TB meningitis and TB per- ter beginning DR-TB treatment.67 icarditis is recommended, although questions on the op- timal dosage, duration and its different effects on HIV- Immune reconstitution inflammatory syndrome positive (on ART and not on ART) as well as HIV-nega- (IRIS) tive people are yet to be answered.54 The commencement of ART in TB/HIV co-infected pa- tients while on anti-TB regimen can sometimes result in MDR TB and HIV management a paradoxical reaction due to rapid recovery of immune The first- ever national drug resistance survey in Ghana function that leads to an inflammatory reaction. This re- in 2016; reported the proportions of drug-resistant TB to action usually occurs within three months of ART regi- be 1.5% and 7% for new cases and previously treated men. It is often among patients who are initiated on ART cases, respectively.13 The resistance of certain MTBC or- at an early stage. Characteristic features include exacer- ganisms to isoniazid and rifampicin characterises multi- bation of active TB symptoms like cough, night sweats, drug resistance TB; resistance to these two drugs extend- tuberculous abscesses, and enlargement of lymph nodes. ing to any fluoroquinolone and at least one of the second The other form of IRIS (unmasking), occurs in patients line injectable drugs is extensively drug-resistant TB. with subclinical TB that becomes reactivated after initi- These two conditions greatly threaten the progress ating ART.68,69 needed to realise the goals set in the End TB Strategy. Coupled with HIV infection, there is an increased risk of Patients with advanced HIV infection may also show adverse treatment outcome with case-fatality rates, some- similar signs and symptoms such as treatment failure or times exceeding 90%, especially when the regimen is drug resistance, making the diagnosis of IRIS challeng- without ART. It is therefore important to screen all ing. The occurrence of paradoxical reactions is not exclu- TB/HIV patients for resistance before starting TB regi- sive to persons with dual infection. Ten per cent and 28% men in order to optimise outcome by providing the ap- of HIV-negative and HIV-positive patients developed propriate treatment regimen. On the contrary, universal paradoxical reactions in one study.70 The diagnosis of screening may not be feasible in resource-limited set- IRIS can be made after excluding other conditions which tings, in which case DST may be limited to patients with may be responsible for clinical deterioration. Its manage- treatment failure or those who are at a high risk of drug- ment usually depends on the degree of severity of the resistant TB.54 signs and symptoms. ART may be continued whilst treat- ing IRIS with one of several options, including cortico- A conventional regimen of at least 20 months of therapy steroids or non-steroidal anti-inflammatory drugs.67 Con- was initially recommended for all MDR-TB cases 40,65 tinuation of anti-TB and ART is encouraged and close until recently when there was a movement towards a monitoring critical in optimising outcome. shorter duration of nine to twelve months for patients who have not been treated previously with the second- 193 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article CONCLUSION AIDS_FactSheet_en.pdf The syndemic interaction between Tuberculosis and HIV 17. GHS, NACP. Guidelines for antiretroviral has contributed significantly to morbidity and mortality therapy in Ghana. 2016. globally; disproportionately affecting Africans. Under- 18. UNAIDS. Country factsheets - Ghana 2016. standing the dual biology of HIV and TB co-infection to- 2017. gether and evidence-based approaches for clinical man- 19. Ghana AIDS Commission. Summary of the 2016 agement is essential for improved outcomes. Although HIV sentinel survey report [Internet]. 2016 [cited adequate control of the TB-HIV co-infection is a daunt- 2018 Jul 3]. Available from: ing task, identification of cases of co-infected patients, http://www.ghanaids.gov.gh/gac1/aids_info.php including MDR-TB, is an important step to providing op- 20. World Health Organization. Global tuberculosis timal treatment and elimination of TB and HIV. report 2019 [Internet]. Geneva; 2019. Available from: REFERENCES https://apps.who.int/iris/bitstream/handle/10665/ 1. Daniel T. The history of tuberculosis. Respir 329368/9789241565714-eng.pdf?ua=1 Med. 2006;100:1862–70. 21. Ministry of Health. The National TB Health 2. WHO. Global Tuberculosis Report 2018. Sector Strategic Plan for Ghana, 2009-2013. Geneva; 2018. 2008. 3. WHO. Global tuberculosis report 2017. 2017. 22. WHO. Ghana tuberculosis profile 2015. 2015. 4. Sulis G, Centis R, Sotgiu G, Ambrosio LD, 23. Ghana Health Service. Guidelines for the clinical Pontali E, Spanevello A, et al. Recent management of TB and HIV co-infection in developments in the diagnosis and management Ghana. 2007. of tuberculosis. Prim Care Respir Med. 2016;26. 24. Cambau E, Drancourt M. Steps towards the 5. WHO. Global Tuberculosis Report 2015. 2015. discovery of Mycobacterium tuberculosis by 6. WHO. The End TB Strategy. 2015. Robert. Eur Soc Clin Infect Dis [Internet]. 7. WHO. Global Tuberculosis Report 2016 2014;20(3):196–201. Available from: [Internet]. 2016. Available from: http://dx.doi.org/10.1111/1469-0691.12555 http://scholar.google.com/scholar?hl=en&btnG= 25. Cudahy P, Shenoi S. Diagnostics for pulmonary Search&q=intitle:No+Title#0 tuberculosis. Postgr Med J. 2016;92(1086):187– 8. WHO. Global tuberculosis report 2017. 2017. 93. 9. Chatterjee D, Pramanik AK. Tuberculosis in the 26. Steingart KR, Henry M, Ng V, Hopewell PC, African continent: a comprehensive review. Ramsay A, Cunningham J, et al. Fluorescence Pathophysiology [Internet]. 2015;22(1):73–83. versus conventional sputum smear microscopy 10. Zumla A, Abubakar I, Raviglione M, Hoelscher for tuberculosis : a systematic review. Lancet M, Ditiu L, McHugh TD, et al. Drug-resistant Infect Dis. 2006;6(September). tuberculosis-current dilemmas, unanswered 27. WHO. Treatment of tuberculosis: guidelines questions, challenges and priority needs. J Infect [Internet]. 4Th Edition. 2010. Available from: Dis. 2012;205. http://www.ncbi.nlm.nih.gov/books/NBK13874 11. Wells W a, Boehme CC, Cobelens FGJ, Daniels 1/#ch2.s3 C, Dowdy D, Gardiner E, et al. Aligning new t 28. Davis JL, Cattamanchi A, Cuevas L., Hopewell uberculosis drug regimens and drug P., Steingart K. Diagnostic accuracy of same-day susceptibility testing: a needs assessment and microscopy versus standard microscopy for roadmap for action. Lancet Infect Dis. pulmonary tuberculosis: a systematic review and 2013;13(5):449–58. meta-analysis. Lancet Infect Dis. 2014;13(2):1– 12. WHO. Ghana tuberculosis profile 2016. 2016. 16. 13. WHO. Ghana tubercuosis profile 2014. 2014. 29. Keshavjee S, Farmer PE. Tuberculosis, drug 14. GHS. Ghana Health Service- 2016 annual report. resistance and the history of modern medicine. N 2017. Engl J Med. 2012;367(10):931–6. 15. Montagnier L. A history of HIV discovery. 30. Dinnes J, Deeks J, Kunst H, Gibson A, Cummins Science (80- ). 2002;298. E, Waugh N, et al. A systematic review of rapid 16. UNAIDS. 2017 Global HIV Statistics [Internet]. diagnostic tests for the detection of tuberculosis 2018. Available from: infection. Health Technol Assess (Rockv) http://www.unaids.org/sites/default/files/media_ [Internet]. 2007;11(3). asset/UNAIDS_FactSheet_en.pdf%0Ahttp://ww 31. WHO. Implementing tuberculosis diagnostics. w.unaids.org/sites/default/files/media_asset/UN 2015. 32. Walters E, Demers A, Zalm MM Van Der, Gie 194 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article RP, Hesseling C. Stool culture for diagnosis of 2015;15(407):1–10. pulmonary tuberculosis in children. J Clin 45. Lawn SD. Point-of-care detection of Microbiol. 2017;55(12):3355–65. lipoarabinomannan (LAM) in urine for diagnosis 33. Lawn SD, Nicol MP. Xpert MTB/RIF assay: of HIV-associated tuberculosis : a state of the art development, evaluation and implementation of review. BMC Infect Dis [Internet]. 2012;12(1):1. a new rapid molecular diagnostic for tuberculosis 46. WHO. The use of lateral flow urine and rifampicin resistance. Futur Microbiol. lipoarabinomannan assay (LF-LAM) for the 2011;6(9):1067–82. diagnosis and screening of active tuberculosis in 34. WHO. Xpert MTB/RIF implementation manual. people living with HIV. 2015. 2014. 47. WHO. Consolidated guidelines on the use of 35. WHO. WHO Meeting Report of a Technical antiretroviral drugs for treating and preventing Expert Consultation: Non-inferiority analysis of HIV infection - recommendations for a public Xpert MTB/RIF Ultra compared to Xpert health approach. 2016. MTB/RIF [Internet]. 2017. Available from: 48. Pathmanathan I, Ahmedov S, Pevzner E, http://apps.who.int/iris/bitstream/10665/254792/ Anyalechi G, Modi S, Kirking H, et al. TB 1/WHO-HTM-TB-2017.04-eng.pdf?ua=1 preventive therapy for people living with HIV: 36. Lawn SD, Kerkhoff AD, Vogt M, Ghebrekristos key considerations for scale-up in resource- Y, Whitelaw A, Wood R. Characteristics and limited settings. Int J Tuberc Lung Dis. early outcomes of patients with xpert MTB/RIF- 2018;22(6):596–605. negative pulmonary tuberculosis diagnosed 49. Mugomeri E, Olivier D, van den Heever WM. during screening before antiretroviral therapy. Health system challenges affecting the Clin Infect Dis. 2012;54(8):1071–9. implementation of isoniazid preventive therapy 37. Creswell J, Codlin AJ, Andre E, Micek MA, in people living with HIV in Lesotho. HIV AIDS Bedru A, Carter EJ, et al. Results from early Rev [Internet]. 2018;17(4):299–307. programmatic implementation of Xpert 50. WHO. Latent tuberculosis infection- updated MTB/RIF testing in nine countries. BMC Infect consolidated guidelines for programmatic Dis [Internet]. 2014;14(2). management. 2018. 38. Scott L, da Silva P, Boehme C., Stevens W, 51. WHO, UNAIDS. Provisional WHO/UNAIDS Gilpin C. Diagnosis of opportunistic infections: secretariat recommendations on the use of HIV co-infection: tuberculosis. Curr Opin HIV cotrimoxazole prophylaxis in adults and children AIDS. 2017;12(2). living with HIV/AIDS in Africa. 2000. 39. Creswell J, Rai B, Wali R, Sudrungrot S, 52. Wiktor SZ, Sassan-morokro M, Grant AD, Adhikari LM, Pant R, et al. Introducing new Abouya L, Karon JM, Maurice C, et al. Efficacy tuberculosis diagnostics: the impact of Xpert® of trimethoprim-sulphamethoxazole prophylaxis MTB/RIF testing on case notifications in Nepal. to decrease morbidity and mortality in HIV-1- Int J Tuberc Lung Dis. 2015;19(5):545–51. infected patients with tuberculosis in Abidjan , 40. WHO. Guidelines for the programmatic Côte d ’ Ivoire : a randomised controlled trial. management of drug-resistant tuberculosis: Lancet. 1999;353:1469–75. emergency update. 2008. 53. WHO. Guidelines on co-trimoxazole 41. WHO. The use of molecular line probe assays for prophylaxis for HIV-related infections among the detection of resistance to second-line anti- children, adolescent and adults. 2006. tuberculosis drugs. 2016. 54. WHO. Guidelines for treatment of drug- 42. WHO. The use of molecular line probe assays for susceptible tuberculosis and patient care. 2017. the detection of resistance to isoniazid and 55. Ford N, Meintjes G, Vitoria M, Greene G, Chiller rifampicin. 2016. T. The evolving role of CD4 cell counts in HIV 43. Sharma SK, Mohan A, Kadhiravan T. HIV-TB care. Curr Opin HIV AIDS. 2017;12(2):123–8. co-infection : epidemiology, diagnosis & 56. Ministry of Health, Ghana Health Service. management. Indian J Med Res. 2005;121:550– Guidelines for Antiretroviral Therapy in Ghana. 67. 2002. 44. Bjerrum S, Kenu E, Lartey M, Newman MJ, 57. INSIGHT START Study Group. Initiation of Addo KK. Diagnostic accuracy of the rapid urine antiretroviral therapy in early asymptomatic HIV lipoarabinomannan test for pulmonary infection. N Engl J Med. 2015;373(9). tuberculosis among HIV-infected adults in 58. TEMPRANO ANRS 12136 Study Group. A trial Ghana – findings from the DETECT HIV-TB of early antiretrovirals and isoniazid preventive study. BMC Infect Dis [Internet]. therapy in Africa. N Engl J Med. 195 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license. Special Article 2015;373(9):808–22. Dis. 2010;4(March):1288–99. 59. WHO. Treatment of tuberculosis: guidelines for 65. WHO. Guidelines for the programmatic national programmes. 2003. management of drug-resistant tuberculosis. 2011; 60. Abdool Karim SS, Naidoo K, Grobler A, 66. WHO. WHO treatment guidelines for drug- Padayatchi N, Baxter C, Gray AL, et al. resistant tuberculosis 2016. 2016. Integration of antiretroviral therapy with 67. WHO. Guidelines for the programmatic tuberculosis treatment. N Engl J Med. management of drug-resistant tuberculosis. 2011;365(16):1492–501. 2008. 61. Havlir D, Kendall MA, Ive P, Kumwenda J, 68. Lee S, Meintjes GR, Kamarulzaman AD, Leung Swindles S, Qasba S, et al. Timing of C. Management of tuberculosis and latent antiretroviral therapy for HIV-1 infection and tuberculosis infection in human tuberculosis. N Engl J Med. 2011;365(16):1482– immunodeficiency virus-infected persons. 91. Respirology. 2013;18:912–22. 62. WHO. Guidance for national tuberculosis 69. WHO. Improving the diagnosis an treatment of programmes on the management of tuberculosis smear negative pulmonary and extrapulmonary in children. 2006. tuberculosis among adults and adolescents. 2007. 63. WHO. Treatment of tuberculosis- guidelines for 70. Breen RAM, Smith CJ, Bettinson H, Dart S, national programmes. 1997. Bannister B, Johnson MA, et al. Paradoxical 64. Khan FA, Minion J, Pai M, Royce S, Burman W, reactions during tuberculosis treatment in Harries AD, et al. Treatment of active patients with and without HIV co-infection. tuberculosis in HIV-coinfected patients : a Thorax. 2004;704–7. systematic review and meta-analysis. Clin Infect 196 www.ghanamedj.org Volume 54 Number 3 September 2020 Copyright © The Author(s). This is an Open Access article under the CC BY license.